Therapeutic quniazoline derivatives

ABSTRACT

Quinazoline derivatives of formula (I): wherein A is 6-membered heteroaryl containing a nitrogen atom and optionally containing one or two further nitrogen atoms; compositions containing them, processes for their preparation and their use in therapy.

The present invention relates to certain quinazoline derivatives for usein the treatment of certain diseases in particular to proliferativedisease such as cancer and in the preparation of medicaments for use inthe treatment of proliferative disease, to novel quinazoline compoundsand to processes for their preparation, as well as pharmaceuticalcompositions containing them as active ingredient.

Cancer (and other hyperproliferative disease) is characterised byuncontrolled cellular proliferation. This loss of the normal regulationof cell proliferation often appears to occur as the result of geneticdamage to cellular pathways that control progress through the cellcycle.

In eukaryotes, an ordered cascade of protein phosphorylation is thoughtto control the cell cycle. Several families of protein kinases that playcritical roles in this cascade have now been identified. The activity ofmany of these kinases is increased in human tumours when compared tonormal tissue. This can occur by either increased levels of expressionof the protein (as a result of gene amplification for example), or bychanges in expression of co activators or inhibitory proteins.

The first identified, and most widely studied of these cell cycleregulators have been the cyclin dependent kinases (or CDKs). Activity ofspecific CDKs at specific times is essential for both initiation andcoordinated progress through the cell cycle. For example, the CDK4protein appears to control entry into the cell cycle (the G0-G1-Stransition) by phosphorylating the retinoblastoma gene product pRb. Thisstimulates the release of the transcription factor E2F from pRb, whichthen acts to increase the transcription of genes necessary for entryinto S phase. The catalytic activity of CDK4 is stimulated by binding toa partner protein, Cyclin D. One of the first demonstrations of a directlink between cancer and the cell cycle was made with the observationthat the Cyclin D1 gene was amplified and cyclin D protein levelsincreased (and hence the activity of CDK4 increased) in many humantumours (Reviewed in Sherr, 1996, Science 274: 1672-1677; Pines, 1995,Seminars in Cancer Biology 6: 63-72). Other studies (Loda et al., 1997,Nature Medicine 3(2): 231-234; Gemma et al., 1996, International Journalof Cancer 68(5): 605-11; Elledge et al. 1996, Trends in Cell Biology 6;388-392) have shown that negative regulators of CDK function arefrequently down regulated or deleted in human tumours again leading toinappropriate activation of these kinases.

More recently, protein kinases that are structurally distinct from theCDK family have been identified which play critical roles in regulatingthe cell cycle and which also appear to be important in oncogenesis.These include the newly identified human homologues of the Drosophilaaurora and S.cerevisiae Ip11 proteins. The three human homologues ofthese genes Aurora-A, Aurora-B and Aurora-C (also known as aurora2,auroral and aurora3 respectively) encode cell cycle regulatedserine-threonine protein kinases (summarised in Adams et al., 2001,Trends in Cell Biology. 11(2): 49-54). These show a peak of expressionand kinase activity through G2 and mitosis. Several observationsimplicate the involvement of human auroraprotemsin cancer. The Aurora-Agene maps to chromosome 20q13, a region that is frequently amplified inhuman tumours including both breast and colon tumours. Aurora-A may bethe major target gene of this amplicon, since Aurora-A DNA is amplifiedand mRNA overexpressed in greater than 50% of primary human colorectalcancers. In these tumours Aurora-A protein levels appear greatlyelevated compared to adjacent normal tissue. In addition, transfectionof rodent fibroblasts with human Aurora-A leads to transformation,conferring the ability to grow in soft agar and form tumours in nudemice (Bischoffet al., 1998, The EMBO Journal. 17(11): 3052-3065). Otherwork (Zhou et al., 1998, Nature Genetics. 20(2): 189-93) has shown thatartificial overexpression of Aurora-A leads to an increase in centrosomenumber and an increase in aneuploidy, a known event in the developmentof cancer. Further work has shown an increase in expression of Aurora-B(Adams et al., 2001, Chromsoma. 110(2):65-74) and Aurora-C (Kimura etal., 1999, Journal of Biological Chemistry, 274(11): 7334-40) in tumourcells when compared to normal cells.

Importantly, it has also been demonstrated that abrogation of Aurora-Aexpression and function by antisense oligonucleotide treatment of humantumour cell lines (WO 97/22702 and WO 99/37788) leads to cell cyclearrest and exerts an antiproliferative effect in these tumour celllines. Additionally, small molecule inhibitors of Aurora-A and Aurora-Bhave been demonstrated to have an antiproliferative effect in humantumour cells (Keen et al. 2001, Poster #2455, American Association ofCancer research annual meeting), as has selective abrogation of Aurora-Bexpression alone by siRNA treatment (Ditchfield et al. 2003. Journal ofCell Biology, 161(2): 267-280). This indicates that inhibition of thefunction of Aurora-A and/or Aurora-B will have an antiproliferativeeffect that may be useful in the treatment of human tumours and otherhyperproliferative disease. Further, inhibition of Aurora kinases as atherapeutic approach to these diseases may have significant advantagesover targeting signalling pathways upstream of the cell cycle (e.g.those activated by growth factor receptor tyrosine kinases such asepidermal growth factor receptor (EGFR) or other receptors). Since thecell cycle is ultimately downstream of all of these diverse signallingevents, cell cycle directed therapies such as inhibition of Aurorakinases would be predicted to be active across all proliferating tumourcells, whilst approaches directed at specific signalling molecules (e.g.EGFR) would be predicted to be active only in the subset of tumour cellswhich express those receptors. It is also believed that significant“cross talk” exists between these signalling pathways meaning thatinhibition of one component may be compensated for by another.

A number of quinazoline derivatives have been proposed hitherto for usein the inhibition of various kinases. For example, WO 96/09294, WO96/15118 and WO 99/06378 describe the use of certain quinazolinecompounds as receptor tyrosine kinase inhibitors, which may be useful inthe treatment of proliferative disease and WO 00/21955 discloses certainquinazoline derivatives as inhibitors of the effects of VEGF.

Quinazoline derivatives have also been disclosed for use in theinhibition of Aurora-A kinase. WO 01/21597 discloses quinazolinederivative bearing a 6-membered aromatic ring containing at least onenitrogen atom. However despite the compounds of WO 01/21597 there stillexists the need for further compounds having Aurora kinase inhibitoryproperties.

The applicants have been successful in finding a novel series ofcompounds which inhibit the effects of the Aurora kinases and inparticular Aurora-A and/or Aurora-B kinase and which have certainproperties that make them particularly useful in formulating medicamentsfor the treatment of disease. In particular the compounds are of use inthe treatment of proliferative disease such as cancer. The compound areuseful in treating either solid or haematological tumours where Aurorakinases are known to be active, and especially in diseases such ascolorectal, breast, lung, prostate, pancreatic or bladder and renalcancer as well as leukemias and lymophomas.

According to one aspect of the present invention there is provided acompound of formula (I):

-   wherein A is 6-membered heteroaryl containing a nitrogen atom and    optionally containing one or two further nitrogen atoms;-   X is O, S, S(O), S(O)₂ or NR¹⁴;-   m is 0, 1, 2, 3 or 4;-   Y is a group selected from O, NR⁵ CO, CONR⁵, CR⁶R⁷ CONR⁵ and    CR⁶R⁷NR⁵;-   Z is a group selected from —NR¹R², phosphonooxy, C₃₋₆cycloalkyl    which C₃₋₆cycloalkyl is substituted by phosphonooxy or C₁₋₄alkyl    substituted by phosphonooxy, and a 4- to 7-membered ring linked via    a carbon atom containing a nitrogen atom and optionally containing a    further nitrogen atom, which ring may be saturated, unsaturated or    partially saturated which ring is substituted on carbon or nitrogen    by phosphonooxy or C₁₋₄alkyl (substituted by phosphonooxy) and which    ring is optionally further substituted on carbon or nitrogen by 1, 2    or 3 halo or C₁₋₄alkyl groups;-   R¹ is a group selected from —COR⁸, —CONR⁸R⁹ and C₁₋₆alkyl which    C₁₋₆alkyl is substituted by phosphonooxy and optionally further    substituted by 1 or 2 halo or methoxy groups;-   R² is a group selected from hydrogen, —COR¹⁰, —CONR¹⁰OR¹¹ and    C₁₋₆alkyl which C₁₋₆alkyl is optionally substituted by 1, 2 or 3    halo or C₁₋₄alkoxy groups, —S(O)_(p)R¹¹ (where p is 0, 1 or 2) or    phosphonooxy, or R² is a group selected from Q₂₋₆alkenyl,    C₂₋₆alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl;-   or R¹ and R² together with the nitrogen to which they are attached    form a 4- to 7-membered ring optionally containing a further    nitrogen atom which ring may be saturated, unsaturated or partially    saturated which ring is substituted on carbon or nitrogen by a group    selected from phosphonooxy and C₁₋₄alkyl substituted by phosphonooxy    or —NR⁸R⁹, and which ring is optionally further substituted on    carbon or nitrogen by 1, 2 or 3 halo or C₁₋₄alkyl groups;-   R³ is a group selected from hydrogen, halo, cyano, nitro,    C₁₋₆alkoxy, C₁₋₆alkyl, —OR¹², —CHR¹²R¹³, —OC(O)R¹², —C(O)R¹²,    —NR¹²C(O)R¹³, —C(O)NR¹²R¹³, —NR¹²SO₂R¹³ and —NR¹²R¹³,-   R⁴ is hydrogen or a group selected from C₁₋₄alkyl, heteroaryl,    heteroarylC₁₋₄alkyl, aryl and arylC₁₋₄alkyl which group is    optionally substituted by 1, 2 or 3 substitutents selected from    halo, methyl, ethyl, cyclopropyl and ethynyl;-   R⁵ is a group selected from hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl,    C₂₋₄alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl;-   R⁶ and R⁷ are independently selected from hydrogen, halo, C₁₋₄alkyl,    C₃₋₆cycloalkyl, hydroxy and C₁₋₄alkoxy;-   R⁸ is C₁₋₄-alkyl substituted by phosphonooxy and optionally further    substituted by 1 or 2 halo or methoxy groups;-   R⁹ is selected from hydrogen and C₁₋₄alkyl;-   R¹⁰ is selected from hydrogen and C₁₋₄alkyl which C₁₋₄alkyl is    optionally substituted by halo, C₁₋₄alkoxy, S(O)_(q) (where q is 0,    1 or 2) or phosphonoxy;-   R¹¹, R¹², R¹³ and R¹⁴ are independently selected from hydrogen,    C₁₋₄alkyl and heterocyclyl; or a pharmaceutically acceptable salt    thereof.

Within the present invention, it is to be understood that, insofar ascertain compounds of formula (I) herein defined may exist in opticallyactive or racemic forms by virtue of one or more asymmetric carbon orsulphur atoms, the invention includes in its definition any suchoptically active or racemic form which possesses Aurora kinaseinhibitory activity and in particular Aurora-A and/or Aurora-B kinaseinhibitory activity. The synthesis of optically active forms may becarried out by standard techniques of organic chemistry well known inthe art, for example by synthesis from optically active startingmaterials or by resolution of a racemic form. Similarly, theabove-mentioned activity may be evaluated using the standard laboratorytechniques referred to herein.

Within the present invention it is to be understood that a compound offormula (I) or a salt thereof may exhibit the phenomenon of tautomerismand that the formulae drawings within this specification can representonly one of the possible tautomeric forms. It is to be understood thatthe invention encompasses any tautomeric form which has Aurora kinaseinhibitory activity and in particular Aurora-A and/or Aurora-B kinaseinhibitory activity and is not to be limited merely to any onetautomeric form utilised within the formulae drawings.

It is also to be understood that certain compounds of formula (I) andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which have Aurora kinase inhibitoryactivity and in particular Aurora-A and/or Aurora-B kinase inhibitoryactivity.

The present invention relates to the compounds of formula (I) as hereindefined as well as to the salts thereof Salts for use in pharmaceuticalcompositions will be pharmaceutically acceptable salts, but other saltsmay be useful in the production of the compounds of formula (I) andtheir pharmaceutically acceptable salts. Pharmaceutically acceptablesalts of the invention may, for example, include acid addition salts ofcompounds of formula (I) as herein defined which are sufficiently basicto form such salts. Such acid addition salts include but are not limitedto furmarate, methanesulphonate, hydrochloride, hydrobromide, citrateand maleate salts and salts formed with phosphoric and sulphuric acid.In addition where compounds of formula (I) are sufficiently acidic,salts are base salts and examples include but are not limited to, analkali metal salt for example sodium or potassium, an alkaline earthmetal salt for example calcium or magnesium, or organic amine salt forexample triethylamine, ethanolamine, diethanolamine, triethanolamine,morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine oramino acids such as lysine.

The compounds of formula (I) may also be provided as in vivohydrolysable esters. An in vivo hydrolysable ester of a compound offormula (I) containing carboxy or hydroxy group is, for example apharmaceutically acceptable ester which is cleaved in the human oranimal body to produce the parent acid or alcohol. Such esters can beidentified by administering, for example, intravenously to a testanimal, the compound under test and subsequently examining the testanimal's body fluid.

Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆alkoxymethyl esters for example methoxymethyl; C₁₋₆alkanoyloxymethylesters for example pivaloyloxymethyl, phthalidyl esters;C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

Suitable pharmaceutically acceptable esters for hydroxy includeinorganic esters such as phosphate esters (including phosphoramidiccyclic esters) and α-acyloxyalkyl ethers and related compounds which asa result of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group/s. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy includeC₁₋₁₀alkanoyl, for example formyl, acetyl, benzoyl, phenylacetyl,substituted benzoyl and phenylacetyl; C₁₋₁₀alkoxycarbonyl (to give alkylcarbonate esters), for example ethoxycarbonyl; di-C₁₋₄alkylcarbamoyl andN-(di-C₁₋₄alkylaminoethyl)-N-C₁₋₄alkylcarbamoyl (to give carbamates);di-C₁₋₄alkylaminoacetyl and carboxyacetyl. Examples of ring substituentson phenylacetyl and benzoyl include aminomethyl, C₁₋₄alkylaminomethyland di-(C₁₋₄alkyl)aminomethyl, and morpholino or piperazino linked froma ring nitrogen atom via a methylene linking group to the 3- or4-position of the benzoyl ring. Other interesting in vivo hydrolysableesters include, for example, R^(A)C(O)OC₁₋₆alkyl-CO—, wherein R^(A) isfor example, benzyloxy-C₁₋₄alkyl, or phenyl. Suitable substituents on aphenyl group in such esters include, for example,4-C₁₋₄piperazino-C₁₋₄alkyl, piperazino-C₁₋₄alkyl andmorpholino-C₁₋₄alkyl.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for the straightchain version only and references to individual branched-chain alkylgroups such as “tert-butyl” are specific for the branched chain versiononly. An analogous convention applies to other generic terms, forexample “alkenyl” and “alkynyl”.

“Cycloalkyl” is a monocyclic, saturated alkyl ring and “aryl” is amonocyclic or bicyclic aromatic ring.

Unless otherwise specified “heteroaryl” is a monocyclic or bicyclicaromatic ring containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ringatoms are chosen from nitrogen, sulphur or oxygen where a ring nitrogenor sulphur may be oxidised.

“Heterocyclyl” is a saturated, unsaturated or partially saturated,monocyclic or bicyclic ring containing 4 to 12 atoms of which 1, 2, 3 or4 ring atoms are chosen from nitrogen, sulphur or oxygen, which ring maybe carbon or nitrogen linked, wherein a —CH₂-group can optionally bereplaced by a —C(O)—; wherein a ring nitrogen or sulphur atom isoptionally oxidised to form the N-oxide or S-oxide(s); wherein a ring—NH is optionally substituted by acetyl, formyl, methyl or mesyl; andwhich a ring is optionally substituted by one or more halo.

“Phosphonooxy” is in one aspect a group of formula —OP(O)(OH)₂. Howeverthe term “phosphonooxy” also includes salts of this group such as thoseformed with alkali metal ions such as sodium or potassium ions oralkaline earth metal ions, for example calcium or magnesium ions.

Where optional substituents are chosen from “1 or 2”, from “1, 2, or 3”or from “1, 2, 3 or 4” groups or substituents it is to be understoodthat this definition includes all substituents being chosen from one ofthe specified groups i.e. all substitutents being the same or thesubstituents being chosen from two or more of the specified groups i.e.the substitutents not being the same.

Compounds of the present invention have been named with the aid ofcomputer software (ACD/Name version 6.6 or ACD Name Batch version 6.0).

Suitable values for any R group (R¹ to R¹⁴) or any part or substitutentfor such groups include:

-   for C₁₋₄alkyl: methyl, ethyl, propyl, isopropyl, butyl,    2-methylpropyl and tert-butyl;-   for C₁₋₆alkyl: C₁₋₄alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl    and hexyl;-   for C₂₋₄alkenyl: vinyl, allyl and 1-propenyl;-   for C₂₋₆alkenyl: C₂₋₄alkenyl, 1-butenyl, 2-butenyl, 3-butenyl,    2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and    4-hexenyl;-   for C₂₋₄alkynyl: ethynyl, 1-propynyl, 2-propynyl and 3-butynyl;-   for C₂₋₆alkynyI: C₂₋₄alkynyl, 2-pentynyl, hexynyl and    1-methylpent-2-ynyl;-   for C₃₋₆cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and    cyclohexyl;-   for C₃₋₆cycloalkylC₁₋₄alkyl: cyclopropylmethyl, cyclopropylethyl,    cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl;-   for aryl: phenyl and naphthyl;-   for arylC₁₋₄alkyl: benzyl, phenethyl, naphthylmethyl and    naphthylethyl;-   for halo: fluoro, chloro, bromo and iodo;-   for C₁₋₄alkoxy: methoxy, ethoxy, propoxy and isopropoxy;-   for C₁₋₆alkoxy: C₁₋₄alkoxy, pentyloxy, 1-ethylpropoxy and hexyloxy;-   for heteroaryl: pyridyl, imidazolyl, quinolinyl, cinnolyl,    pyrimidinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, triazolyl,    oxazolyl, isoxazolyl and pyrazinyl; preferably thiazolyl, pyridyl,    imidazolyl and pyrimidinyl; and more preferably pyridyl and    pyrimidinyl;-   for heteroarylC₁₋₄alkyl: pyridylmethyl, pyridylethyl,    pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl,    imidazolylpropyl, imidazolylbutyl, quinolinylpropyl,    1,3,4-triazolylpropyl and oxazolylnethyl;-   for heterocyclyl: furyl, thienyl, pyrrolyl, pyrrolidinyl,    imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl,    pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,    quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl,    benzoxazolyl, benzothienyl, benzofuryl, piperidinyl,    N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl,    N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl,    oxetanyl, morpholinyl, tetrahydroisoquinolinyl,    tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl,    tetrahydrofuranyl, 2,5-dioximidazolidinyl,    2,2-dimethyl-1,3-dioxolanyl and 3,4-dimethylenedioxybenzyl.

It should be noted that examples given for terms used in the descriptionare not limiting.

Preferred values of A, X, m, Y, Z, R³ and R⁴ are as follows. Such valuesmay be used where appropriate with any of the definitions, claims orembodiments defined herein.

In one aspect of the invention A is pyridyl or pyrimidinyl. In a furtheraspect A is a group of formula (a), (b), (c) or (d):

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the Y group of formula (I). In a preferredaspect A is a group of formula (b) or (d).

In one aspect of the invention X is NR¹⁴, O or S. In another aspect X isNR¹⁴. In yet another aspect X is NH.

In one aspect of the invention m is 0, 2, 3 or 4. In another aspect m is2.

In one aspect of the invention Y is O, NR⁵CO or CR⁶R⁷NR⁵. In anotheraspect Y is O, NHCO or CH₂NH. In a further aspect Y is NHCO

In one aspect of the invention Z is a group selected from —NR¹R²,phosphonooxy, cyclopropyl which cyclopropyl is substituted by C₁₋₄alkylsubstituted by phosphonooxy, and a piperidine or piperazine ring linkedvia carbon which ring is substituted on carbon or nitrogen byphosphonooxy or C₁₋₄alkyl substituted by phosphonooxy. In another aspectZ is a group selected from —NR¹R², phosphonooxy,2-(phosphonooxymethyl)cyclopropyl and1-(2-phosphonooxyethyl)piperidin-4-yl. In another aspect Z is —NR¹R².

In one aspect of the invention R¹ is C₁₋₅alkyl substituted byphosphonooxy. In another aspect R¹ is C₁₋₅alkyl substituted byphosphonooxy and further substituted by 1 or 2 halo. In a further aspectR¹ is 2-phosphonooxyethyl, 2-phosphonooxy-1,1-dimethylethyl,2-phosphonooxy-2-methylethyl, 3-phosphonooxy-1,1-dimethylpropyl,3-phosphonooxypropyl and 4-phosphonooxybutyl. In yet another aspect R¹is 2-phosphonooxyethyl, 3-phosponooxy-1,1-dimethylpropyl or4-phosphonooxybutyl. In a further aspect R¹ is 2-phosphonooxyethyl.

In one aspect of the invention R² is a group selected from hydrogen,C₁₋₆alkyl which C₁₋₆alkyl is optionally substituted by 1, 2 or 3 halo orC₁₋₄alkoxy groups, C₂₋₆alkenyl, C₂₋₆allyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkylC₁₋₄alkyl. In another aspect R² is hydrogen, C₁₋₅alkyl,C₂₋₄alkynyl or C₃₋₆cycloalkyl. In another aspect R² is hydrogen, allyl,2-propynyl, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, butyl,2,2-dimethylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl,cyclobutylmethyl, cyclopentyl, cyclohexyl, cyclopentyltnethyl,3,3,3-trifluoropropyl and 2-methoxyethyl. In yet another aspect R² ishydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, 2,2-dimethylpropyl,cyclopropyl, cyclobutyl, cyclohexyl or prop-2-ynyl. In a further aspectR² is hydrogen, methyl, ethyl isopropyl or cyclohexyl.

In one aspect of the invention R¹ and R² together with the nitrogen towhich they are attached form a saturated 5- to 6-membered ringoptionally containing a further nitrogen atom wherein the ring issubstituted on carbon or nitrogen by a group selected from phosphonooxyand C₁₋₄alkyl (substituted by phosphonooxy or —NR⁸R⁹) and where the ringis optionally further substituted on carbon or nitrogen by 1 or 2C₁₋₄alkyl groups. In another aspect of the invention R¹ and R² togetherwith the nitrogen to which they are attached form a piperidine,pyrrolidine or piperazine ring which is substituted on carbon ornitrogen by a group selected from phosphonooxy, phosphonooxymethyl and2-phosphonooxyethyl and where the ring is optionally further substitutedon carbon or nitrogen by 1 or 2 methyl. In a further aspect of theinvention R¹ and R² together with the nitrogen to which they areattached form 4-(phosphonooxymethyl)piperidinyl,2-(phosphonooxymethyl)piperidinyl, 2-(phosphonooxymethyl)pyrrolidinyl,4-(2-phosphonooxyethyl)piperazinyl, 3-(phosphonooxy)pyrrolidinyl,3-(phosphonooxy)piperidinyl, 4-(phosphonooxy)piperidinyl,4-(2-phosphonooxyethyl)piperidinyl, 2-(2-phosphonooxyethyl)pyrrolidinylor 2-(2-phosphonooxyethyl)piperidinyl. In yet another aspect R¹ and R²together with the nitrogen to which they are attached form2-(phosphonooxymethyl)piperidinyl, 4-(phosphonoxy)piperidinyl,4-(2-phosphonooxyethyl)piperidinyl, 2-(2-phosphonooxyethyl)piperidinyl,2-(phosphonooxymethyl)pyrrolidinyl, 4-(phosphonooxymethyl)piperidinyl or4-(2-phosphonooxyethyl)piperazinyl.

In one aspect of the invention R³ is C₁₋₄alkoxy or hydrogen. In anotheraspect R³ is methoxy or hydrogen. In another aspect R³ is methoxy. Inanother aspect R³ is hydrogen.

In one aspect R⁴ is phenyl or benzyl optionally substituted by 1 or 2 offluoro or chloro. In another aspect R⁴ is 3-fluorophenyl,3-chlorophenyl, 3-chlorobenzyl, 3,5-difluorophenyl, 3,4-difluorophenyl,2-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 3-chloro-4-fluorophenyl and 3-chloro-4-fluorobenzyl.In a further aspect R⁴ is 3-fluorophenyl, 3chlorophenyl, 3-chlorobenzyl,3,4-difluorophenyl, 3-chloro-4-fluorophenyl and 3-chloro4-fluorobenzyl.In yet a further aspect R⁴ is 3-fluorophenyl. In another aspect R⁴ is3-chlorophenyl. In a further aspect R⁴ is 3-chlorobenzyl. In yet anotheraspect R⁴ is 3,4-difluorophenyl. In another aspect R⁴ is3-chloro-4-fluorophenyl. In a further aspect R⁴ is3-chloro-4-fluorobenzyl.

In one aspect R⁵ is hydrogen or methyl. In another aspect R⁵ ishydrogen.

In one aspect of the invention R⁶ is hydrogen, fluoro, chloro or methyl.In another aspect R⁶ is hydrogen.

In one aspect of the invention R⁷is hydrogen, fluoro, chloro or methyl.In another aspect R⁷ is hydrogen.

In one aspect R⁸ is 2-phosphonooxyethyl.

In one aspect of the invention R⁹ is hydrogen, methyl or ethyl.

In one aspect of the invention R¹⁰ is hydrogen, methyl or ethyl.

In one aspect of the invention R¹¹ is hydrogen, methyl or ethyl.

In one aspect of the invention R¹² is hydrogen or methyl.

In one aspect of the invention R¹³ is hydrogen or methyl.

In one aspect of the invention R¹⁴ is hydrogen or methyl.

A preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a), (b), (c) or (d) as defined above;-   X is NH;-   m is 0, 1, 2, 3 or 4;-   Y is O, NR⁵CO or CR⁶R⁷NR⁵-   Z is —NR¹R², phoshonooxy, cyclopropyl which cyclopropyl is    substituted by C₁₋₄alkyl substituted by phosphonooxy, and a    piperidine or piperazine ring linked via a carbon atom which ring is    substituted on carbon or nitrogen by phosphonooxy or C₁₋₄alkyl    substituted by phosphonooxy;-   R¹ is C₁₋₅alkyl substituted by phosphonooxy;-   R² is a group selected from hydrogen, C₁₋₆alkyl which C₁₋₆alkyl is    optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups, C₂₋₆    alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl;-   R³ is C₁₋₄alkoxy or hydrogen;-   R⁴ is phenyl or benzyl optionally substituted by 1 or 2 of fluoro or    chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   or a pharmaceutically acceptable salt thereof.

Another preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (b) or (d) as defined above;-   X is NH;-   m is 0, 1, 2, 3 or 4;-   Y is 0, NR⁵CO or CR⁶R⁷NR⁵-   Z is —NR¹R², phoshonooxy, cyclopropyl which cyclopropyl is    substituted by C₁₋₄alkyl substituted by phosphonooxy, and a    piperidine or piperazine ring linked via a carbon atom which ring is    substituted on carbon or nitrogen by phosphonooxy or C₁₋₄alkyl    substituted by phosphonooxy;-   R¹ is C₁₋₅ alkyl substituted by phosphonooxy;-   R² is hydrogen, C₁₋₅alkyl, C₂₋₄alkynyl or C₃₋₆cycloalkyl;-   R³ is methoxy;-   R⁴ is phenyl or benzyl optionally substituted by 1 or 2 of fluoro or    chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   or a pharmaceutically acceptable salt thereof.

Another preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (a), (b), (c) or (d) as defined above;-   X is NH;-   m is 0, 1, 2, 3 or4;-   Y is O, NR⁵CO or CR⁶R⁷NR⁵-   Z is —NR¹R², phoshonooxy, cyclopropyl which cyclopropyl is    substituted by C₁₋₄alkyl substituted by phosphonooxy, and a    piperidine or piperazine ring which the ring is substituted by    phosphonooxy or C₁₋₄alkyl substituted by phosphonooxy;-   R¹ and R² together with the nitrogen to which they are attached form    a piperidine, pyrrolidine or piperazine ring which ring is    substituted on carbon or nitrogen by a group selected from    phosphonooxy, phosphonooxymethyl and 2-phosphonooxyethyl and which    ring is optionally further substituted on carbon or nitrogen by 1 or    2 methyl.-   R³ is C₁₋₄alkoxy or hydrogen;-   R⁴ is phenyl or benzyl optionally substituted by 1 or 2 of fluoro or    chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   or a pharmaceutically acceptable salt thereof.

A further preferred class of compounds is of formula (I) wherein:

-   A is a group of formula (b) or (d) as defined above;-   X is NH;-   m is 0, 1, 2, 3 or 4;-   Y is O, NR⁵C or CR⁶R⁷NR⁵-   Z is —NR¹R², phoshonooxy, cyclopropyl (substituted by C₁₋₄alkyl    (substituted by phosphonooxy)) and piperidine or piperazine ring    where the ring is substituted by phosphonooxy or C₁₋₄alkyl    (substituted by phosphonooxy);-   R¹ and R² together with the nitrogen to which they are attached form    a piperidine, pyrrolidine or piperazine ring which is substituted on    carbon or nitrogen by a group selected from phosphonooxy,    phosphonooxymethyl and 2-phosphonooxyethyl and where the ring is    optionally further substituted on carbon or nitrogen by 1 or 2    methyl.-   R³ is methoxy;-   R⁴ is phenyl or benzyl optionally substituted by 1 or 2 of fluoro or    chloro;-   R⁵ is hydrogen or methyl; and-   R⁶ and R⁷ are independently hydrogen, fluoro, chloro or methyl;-   or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, a preferred compound of theinvention is any compound selected from:

-   3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyl    dihydrogen phosphate;-   3-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7    yl]oxy}propyl)amino]-3-methylbutyl dihydrogen phosphate;-   2-[(3-{[4-({6-[(3    chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]ethyl    dihydrogen phosphate;-   2-[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7    yl]oxy}propyl)piperidin-2-yl]ethyl dihydrogen phosphate;-   [(2R)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)pyrrolidin-2-yl]methyl    dihydrogen phosphate;-   2-[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxypropyl)piperidin-4-yl]ethyl    dihydrogen phosphate;-   2-[ethyl(3-{[4-({6-[(3-fluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3,4-difluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isopropyl)amino]ethyl    dihydrogen phosphate;-   (3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl    dihydrogen phosphate;-   4-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}butyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(methyl)amino]ethyl    dihydrogen phosphate;-   [1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-2-yl]methyl    dihydrogen phosphate;-   2-[(5-{[4-({6-[(3-chlorobenzoyl)amino)pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}pentyl)(ethyl)amino]ethyl    dihydrogen phosphate;-   4-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]butyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-fluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(methyl)amino)ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isobutyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclopropyl)amino]ethyl    dihydrogen phosphate;-   [1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl]methyl    dihydrogen phosphate;-   2-[4-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperazin-1-yl]ethyl    dihydrogen phosphate;-   [(2S)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-merhoxyquinazoline-7-yl]oxy}propyl)pyrrolidin-2-yl]methyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclobutyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(prop-2-yn-1-yl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclohexyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]ethyl    dihydrogen phosphate;-   3-{4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl    dihydrogen phosphate;-   1-[3-({4-[(2-{[(3-chloro-4-fluorophenyl)amino]methyl}pyrimidin-5-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl    dihydrogen phosphate;-   3-[(3-{4-({2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyl    dihydrogen phosphate;-   2-[(3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(2,2-dimethylpropyl)amino]ethyl    dihydrogen phosphate;-   [2-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)cyclopropyl]methyl    dihydrogen phosphate; and-   2-[4-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)piperidin-1-yl]ethyl    dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.

In another aspect, a more preferred compound is any one selected from:

-   3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyl    dihydrogen phosphate;-   3-[(3-{[4-({6-[(3chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7    yl]oxy}propyl)amino]-3-methylbutyl dihydrogen phosphate;-   2-[(3-{[4-({6-[(3    chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)aminolethyl    dihydrogen phosphate;-   2-[ethyl(3-{[4-({6-[(3-fluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{4-({6-[(3,4-difluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinaolin-7-yl]oxy}propyl)(isopropyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(methyl)amino]ethyl    dihydrogen phosphate;-   2-[(5-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}pentyl)(ethyl)amino]ethyl    dihydrogen phosphate;-   4-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]butyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-fluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(methyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isobutyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclopropyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclobutyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(prop-2-yn-1-yl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclohexyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]ethyl    dihydrogen phosphate;-   3-[(3-{[4-({2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyl    dihydrogen phosphate; and-   2-[(3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(2,2-dimethylpropyl)aminolethyl    dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.

In a further aspect, a more preferred compound is any one selected from:

-   2-[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7    yl]oxy}propyl)piperidin-2-yl]ethyl dihydrogen phosphate;-   [(2R)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)pyrrolidin-2-yl]methyl    dihydrogen phosphate;-   2-[1-(3-{[4-([6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl]ethyl    dihydrogen phosphate;-   (3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl    dihydrogen phosphate;-   [1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]yl]oxy}propyl)piperidin-2-yl]methyl    dihydrogen phosphate;-   [1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl]methyl    dihydrogen phosphate;-   2-[4-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperazin-1-yl]ethyl    dihydrogen phosphate;-   [(2S)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)pyrrolidin-2-yl]methyl    dihydrogen phosphate; and-   1-[3-({4-[(2-{[(3-chloro-4-fluorophenyl)amino]methyl}pyrimidin-5-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yl    dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.

Another more preferred compound is any one selected from:4-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}butyldihydrogen phosphate;

-   3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl    dihydrogen phosphate;-   [2-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)cyclopropyl]methyl    dihydrogen phosphate; and-   2-[4-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)piperidin-1-yl]ethyl    dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.

A particularly preferred compound is any one selected from:

-   2-[(3-{[4-({6-[(3    chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]ethyl    dihydrogen phosphate;-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isobutyl)amino]ethyl    dihydrogen phosphate-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclopropyl)amino]ethyl    dihydrogen phosphate-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclobutyl)amino]ethyl    dihydrogen phosphate-   2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(prop-2-yn-1-yl)amino]ethyl    dihydrogen phosphate-   2-[(3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(2,2-dimethylpropyl)amino]ethyl    dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides a process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, which process comprises converting a compoundof formula (II) into a compound of formula (I) by phosphorylation of anappropriate hydroxy group:

where A, X, m, Y, R³ and R⁴ are as defined for formula (I); and Z′ is agroup selected from —NR^(1′)R^(2′), hydroxy, C₃₋₆cycloalkyl whichC₃₋₆Cycloalkyl is substituted by hydroxy or C₁₋₄alkyl substituted byhydroxy, and a 4- to 7-membered ring linked via a carbon atom,containing a nitrogen atom and optionally containing a further nitrogenatom, which ring may be saturated, unsaturated or partially saturatedand which ring is substituted on carbon or nitrogen by hydroxy orC₁₋₄alkyl substituted by hydroxy and which ring is optionally furthersubstituted on carbon or nitrogen by 1, 2 or 3 halo or C₁₋₄alkyl groups;R^(1′) is a group selected from —COR^(8′), —CONR^(8′)R⁹and C₁₋₆alkylwhich C₁₋₆alkyl is substituted by hydroxy and optionally furthersubstituted by 1 or 2 halo or methoxy groups; R^(2′) is a group selectedfrom hydrogen, —COR¹⁰, —CONR¹⁰OR¹¹ and C₁₋₆alkyl which C₁₋₆alkyl isoptionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups,—S(O)_(p)R¹¹ (where p is 0, 1 or 2) or hydroxy, or R^(2′) is a groupselected from C₂₋₆alkenyl, C₂₋₆alknyl, C₃₋₆ cycloalkyl andC₃₋₆cycloalkylC₁₋₄alkyl; or R^(1′) and R^(2′) together with the nitrogento which they are attached form a 4- to 7- membered ring optionallycontaining a further nitrogen atom which ring may be saturated,unsaturated or partially saturated and which ring is substituted oncarbon or nitrogen by a group selected from hydroxy and C₁₋₄alkyl whichC₁₋₄alkyl is substituted by hydroxy or —NR^(8′)R⁹ and which ring isoptionally further substituted on carbon or nitrogen by 1, 2 or 3 haloor C₁₋₄alkyl groups; and where R^(8′) is C₁₋₄alkyl substituted byhydroxy and optionally further substituted by 1 or 2 halo or methoxygroups: and thereafter if necessary:

-   i) converting a compound of the formula (I) into another compound of    the formula (I); and/or-   ii) removing any protecting groups; and/or-   iii) forming a pharmaceutically acceptable salt thereof.

Phosphorylation may be suitably performed by treatment with 1-Htetrazole (or a suitable replacement such as S-ethyl tetrazole orpyridinium hydrochloride) and di-tert-butyldiethylphosphoramidite ordibenzyldiethylphosphoramidite at 5 to 35° C. under an inert atmospherefor 30 minutes to 4 hours followed by treatment with an oxidizing agentsuch as meta-chloroperbenzoic acid (mCPBA) or 30% aqueous hydrogenperoxide at −10 to 25° C. for 2 to 18 hour. Deprotection of thetert-butyl groups to yield the phosphate group is required as a finalstep with these reagents and may be readily achieved by treatment with4.0 N hydrochloric acid in 1,4-dioxane at 10 to 35° C. for 12 to 18hours.

This process may further comprise a method for the preparation of acompound of formula (II) where Z′ is —NR^(1′)R^(2′) which methodcomprises the reaction of a compound of formula (III) where L is aleaving group such as halo (e.g. chloro):

with an amine of formula (IV):

Suitable reaction conditions for this method include heating a compoundof formula (III) with an excess of amine of formula (IV) in an inertsolvent such as dimethylacetamide, with or without the addition of asuitable catalyst (such as tetra-n-butylarnmoniuim iodide or potassiumiodide) at a temperature of 50 to 100° C. for 12 to 72 hours.

The amines of formula (IV) are known in the art or may be prepared bythe skilled person using methods known in the art.

The process may further comprise a method for the preparation of acompound of formula (III) which method comprises the reaction of acompound of formula (V) where P is a suitable protecting group for ahydroxy group (such as benzyl):

by reaction with a compound of formula (VI) where L′ is a leaving groupsuch as halo (e.g. bromo):

Such a reaction can be achieved (after removal of the protecting groupusing a method selected from those already described in the literature)under a range of conditions described in the literature such as heatinga compound of formula (V) with a compound of formula (VI) in thepresence of a catalyst such as caesium carbonate in a solvent such asacetonitrile at a temperature of 80 to 100° C. for 1 to 4 hours.

The process may further comprise a method for the preparation of acompound of formula (V) where X is NR¹⁴, O or S which method comprisesthe reaction of a compound of formula (VII) where L is a leaving groupsuch as halo (e.g. chloro) and where P is a protecting group for ahydroxy group (such as benzyl):

with a compound of formula (VIII)

Such a reaction can be achieved under a range of conditions described inthe literature such as heating a compound of formula (VII) with acompound of formula (VIII) in a solvent such as isopropanol ordimethylacetamide (optionally in the presence of an acid catalyst suchas hydrochloric acid) at a temperature of 80 to 100° C. for 2 to 6hours. Alternatively the reaction may be effected using a base such assodium hydride and carrying out the reaction in an inert solvent such asdimethylformamide at a temperature of 50 to 80° C. for 2 to 6 hours.

The process may further comprise a method for the preparation of acompound of formula (VII) which method comprises the reaction of acompound of formula (IX) where P is a protecting group for a hydroxygroup (such as benzyl) with a chlorinating agent such as thionylchloride, phosphorus oxychloride or phosphorus pentachloride.

Suitable reaction conditions are illustrated herein.

A method for the preparation of a compound of formula (IX) comprises thereaction of a compound of formula (X) where R′ may be either hydrogen oran alkyl, aryl or benzyl group and where P is a protecting group:

with formamide or a suitable equivalent (such as formamidine acetate).The reaction is suitably effected either by heating a compound offormula (X) in neat formamide or by heating in a suitable solvent suchas 2-methoxyethanol at elevated temperature, conveniently at the refluxtemperature of the solvent.

Compounds of formula (X) are either known compounds or they can beprepared by the skilled person using conventional methods. Inparticular, compounds of formula (X) may be prepared by reduction of thecorresponding nitro compound of formula (XI) where R′ may be eitherhydrogen or an alkyl, aryl or benzyl group:

Suitable reaction conditions are illustrated herein.

Compounds of formula (XI) may be obtained by nitration of a compound offormula (XII)) where R′ may be either hydrogen or an alkyl, aryl orbenzyl group:

for example, using nitric acid as the nitrating agent. Again, suitablereaction conditions are illustrated herein.

The compounds of formula (VIII) are known in the art or may be preparedby the skilled person using methods known in the art. However theprocess may further comprise a method for the preparation of a compoundaccording to formula (VIII) where Y is NR⁵CO and X is NH which methodcomprises the reduction of a compound of formula (XIII)

for example, using hydrogen (in the presence of a platinum or palladiumcatalyst) as a reducing agent. Again, suitable reaction conditions areillustrated herein.

The process may further comprise a method for the preparation of acompound according to formula (XIII) which method comprises the reactionof a compound of formula (XIV)

with a compound of formula (XV) where L is an appropriate leaving group(such as carboxylate, (C₁₋₁₀alkyl)COO or halo, such as chloro):

Again, suitable reaction conditions are illustrated herein.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogen group. Particular examplesof modifications include the reduction of a nitro group to an aminogroup by for example, catalytic hydrogenation with a nickel catalyst ortreatment with iron in the presence of hydrochloric acid with heating;oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound formula (I), or apharmaceutically acceptable salt thereof, as defined herein inassociation with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal track, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, soya bean oil, coconut oil,or preferably olive oil, or any other acceptable vehicle

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible or lyophilised powders and granules suitable for preparationof an aqueous suspension or solution by the addition of water generallycontain the active ingredient together with a dispersing or wettingagent, suspending agent and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose already mentioned above. Additional excipients such as sweetening,flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, solutions, emulsions orparticular systems, which may be formulated according to knownprocedures using one or more of the appropriate dispersing or wettingagents and suspending agents, which have been mentioned above. A sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in polyethylene glycol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedure well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less preferably 5 μm or less and more preferablybetween 5 μm and 1 μm, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For farther information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

Therefore in a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,for use in therapy. Further provided is a compound of formula (I), or apharmaceutically acceptable salt thereof, for use as a medicament. Acompound of formula (I), or a pharmaceutically acceptable salt thereof,is also provided for use in the treatment of a disease where theinhibition of one or more Aurora kinase is beneficial. In particular itis envisaged that inhibition of Aurora-A kinase and/or Aurora-B kinasemay be beneficial. Preferably inhibition of Aurora-B kinase isbeneficial. A compound of formula (I), or a pharmaceutically acceptablesalt thereof, has further use in the treatment of hyperproliferativediseases such as cancer and in particular colorectal, breast, lung,prostate, pancreatic or bladder and renal cancer or leukemias orlymphomas.

Additionally a compound of formula (I), or a pharmaceutically acceptablesalt thereof is provided for use in a method of treatment of awarm-blooded animal such as man by therapy. According to this aspect,there is provided a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use in the method of treating a humansuffering from a disease in which the inhibition of one or more Aurorakinases is beneficial, comprising the steps of administering to a personin need thereof a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof. In particularit is envisaged that inhibition of Aurora-A kinase and/or Aurora-Bkinase may be beneficial. Preferably inhibition of Aurora-B kinase isbeneficial. Further provided is a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the method oftreating a human suffering from a hyperproliferative disease such ascancer and in particular particular colorectal, breast, lung, prostate,pancreatic or bladder and renal cancer or leukemias or lymphomas,comprising the steps of administering to a person in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In another aspect of the invention, there is provided the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof,in the preparation of a medicament for the treatment of a disease wherethe inhibition of one or more Aurora kinase is beneficial. In particularit is envisaged that inhibition of Aurora-A kinase and/or Aurora-Bkinase may be beneficial. Preferably inhibition of Aurora-B kinase isbeneficial. In another aspect of the invention, there is provided theuse of a compound of formula (I) or a pharmaceutically acceptable saltthereof, in the preparation of a medicament for the treatment ofhyperproliferative diseases such as cancer and in particular colorectal,breast, lung, prostate, pancreatic or bladder and renal cancer orleukemias or lymphomas.

For the above mentioned therapeutic uses the dose administered will varywith the compound employed, the mode of administration, the treatmentdesired, the disorder indicated and the age and sex of the animal orpatient. The size of the dose would thus be calculated according to wellknown principles of medicine.

In using a compound of formula (I) for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.05 mg/kg to 50 mg/kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.05 mg/kgto 25 mg/kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.05mg/kg to 25 mg/kg body weight will be used.

The treatment defined herein may be applied as a sole therapy or mayinvolve, in addition to the compound of the invention, conventionalsurgery or radiotherapy or chemotherapy. Such chemotherapy may includeone or more of the following categories of anti-tumour agents:

-   (i) antiproliferative/antineoplastic drugs and combinations thereof,    as used in medical oncology, such as alkylating agents (for example    cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,    melphalan, chlorambucil, busulphan and nitrosoureas);    antimetabolites (for example antifolates such as fluoropyrimidines    like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine    arabinoside and hydroxyurea; antitumour antibiotics (for example    anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,    epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);    antimitotic agents (for example vinca alkaloids like vincristine,    vinblastine, vindesine and vinorelbine and taxoids like taxol and    taxotere); and topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan and camptothecin);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progestogens (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase such as finasteride;-   (iii) Agents which inhibit cancer cell invasion (for example    metalloproteinase inhibitors like marimastat and inhibitors of    urokinase plasminogen activator receptor function);-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies (for example the anti-erbb2 antibody trastizumab    [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyl    transferase inhibitors, tyrosine kinase inhibitors and    serine-threonine kinase inhibitors, for example inhibitors of the    epidermal growth factor family (for example EGFR family tyrosine    kinase inhibitors such as    N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (gefitinib, AZD 1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (erlotinib, OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family;-   (v) antiangiogenic agents such as those which inhibit the effects of    vascular endothelial growth factor, (for example the anti-vascular    endothelial cell growth factor antibody bevacizumab [Avastin™],    compounds such as those disclosed in International Patent    Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)    and compounds that work by other mechanisms (for example linomide,    inhibitors of integrin αvβ3 function and angiostatin);-   (vi) vascular damaging agents such as Combretastatin A4 and    compounds disclosed in International Patent Applications WO    99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and    WO02/08213;-   (vii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-ras antisense;-   (viii) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1 or    BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such    as those using cytosine deamninase, thymidine kinase or a bacterial    nitroreductase enzyme and approaches to increase patient tolerance    to chemotherapy or radiotherapy such as multi-drug resistance gene    therapy; and-   (ix) immunotherapy approaches, including for example ex vivo and iii    vivo approaches to increase the immunogenicity of patient tumour    cells, such as transfection with cytokines such as interleukin 2,    interleukin 4 or granulocyte-macrophage colony stimulating factor,    approaches to decrease T-cell anergy, approaches using transfected    immune cells such as cytokine-tratisfected dendritic cells,    approaches using cytokine-transfected tumour cell lines and    approaches using anti-idiotypic antibodies. In addition a compound    of the invention may be used in combination with one or more cell    cycle inhibitors. In particular with cell cycle inhibitors which    inhibit bub1, bubR1 or CDK. Such conjoint treatment may be achieved    by way of the simultaneous, sequential or separate dosing of the    individual components of the treatment. Such combination products    employ the compounds of this invention within the dosage range    described herein and the other pharmaceutically-active agent within    its approved dosage range.

In addition to their use in therapeutic medicine, the compounds offormula (I) and their pharmaceutically acceptable salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofinhibitors of cell cycle activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

The compounds of the invention inhibit the serine-threonine kinaseactivity of the Aurora kinases, in particular Aurora-A and/or Aurora-Band thus inhibit the cell cycle and cell proliferation. These propertiesmay be assessed for example, using one or more of the procedures set outbelow. Whilst not wishing to be bound by theoretical constraints, it isbelieved that the compounds of formula (I) described herein may act asprodrugs. In procedures (c) and (d) set out below it is believed that aphosphonooxy group present in the compound of formula (I) is cleaved insitu to yield a hydroxy group and that such cleavage is necessary foractivity is these assays.

(a) In Vitro Aurora-A Kinase Inhibition Test

This assay determines the ability of a test compound to inhibitserine-threonine kinase activity. DNA encoding Aurora-A may be obtainedby total gene synthesis or by cloning. This DNA may then be expressed ina suitable expression system to obtain polypeptide with serine-threoninekinase activity. In the case of Aurora-A, the coding sequence wasisolated from cDNA by polymerase chain reaction (PCR) and cloned intothe BamH1 and Not1 restriction endonuclease sites of the baculovirusexpression vector pFastBac HTc (GibcoBRL/Life technologies). The 5′ PCRprimer contained a recognition sequence for the restriction endonucleaseBamH1 5′ to the Aurora-A coding sequence. This allowed the insertion ofthe Aurora-A gene in frame with the 6 histidine residues, spacer regionand rTEV protease cleavage site encoded by the pFastBac HTc vector. The3′ PCR primer replaced the Aurora-A stop codon with additional codingsequence followed by a stop codon and a recognition sequence for therestriction endonuclease Not1. This additional coding sequence (5′ TACCCA TAC GAT GTT CCA GAT TAC GCT TCT TAA 3′) encoded for the polypeptidesequence YPYDVPDYAS. This sequence, derived from the influenzahemagglutin protein, is frequently used as a tag epitope sequence thatcan be identified using specific monoclonal antibodies. The recombinantpFastBac vector therefore encoded for an N-terminally 6 his tagged, Cterminally influenza hemagglutin epitope tagged Aurora-A protein.Details of the methods for the assembly of recombinant DNA molecules canbe found in standard texts, for example Sambrook et al. 1989, MolecularCloning—A Laboratory Manual, 2^(nd) Edition, Cold Spring HarborLaboratory press and Ausubel et al. 1999, Current Protocols in MolecularBiology, John Wiley and Sons Inc.

Production of recombinant virus can be performed followingmanufacturer's protocol from GibcoBRL. Briefly, the pFastBac-1 vectorcarrying the Aurora-A gene was transformed into E. coli DH10Bac cellscontaining the baculovirus genome (bacmid DNA) and via a transpositionevent in the cells, a region of the pFastBac vector containinggentamycin resistance gene and the Aurora-A gene including thebaculovirus polyhedrin promoter was transposed directly into the bacmidDNA. By selection on gentamycin, kanamycin, tetracycline and X-gal,resultant white colonies should contain recombinant bacmid DNA encodingAurora-A. Bacmid DNA was extracted from a small scale culture of severalBH10Bac white colonies and transfected into Spodoptera frugiperda Sf21cells grown in TC100 medium (GibcoBRL) containing 10% serum usingCellFECTIN reagent (GibcoBRL) following manufacturer's instructions.Virus particles were harvested by collecting cell culture medium 72 hrspost transfection. 0.5 mls of medium was used to infect 100 mlsuspension culture of Sf21s containing 1×10⁷ cells/ml. Cell culturemedium was harvested 48 hrs post infection and virus titre determinedusing a standard plaque assay procedure. Virus stocks were used toinfect Sf9 and “High 5” cells at a multiplicity of infection (MOI) of 3to ascertain expression of recombinant Aurora-A protein.

For the large scale expression of Aurora-A kinase activity, Sf21 insectcells were grown at 28° C. in TC100 medium supplemented with 10% foetalcalf serum (Viralex) and 0.2% F68 Pluronic (Sigma) on a Wheaton rollerrig at 3 r.p.m. When the cell density reached 1.2×10⁶ cells ml⁻¹ theywere infected with plaque-pure Aurora-A recombinant virus at amultiplicity of infection of 1 and harvested 48 hours later. Allsubsequent purification steps were performed at 4° C. Frozen insect cellpellets containing a total of 2.0×10⁸ cells were thawed and diluted withlysis buffer (25 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulphonic acid]) pH7.4 at 4°C., 100 mM KCl, 25 mM NaF, 1 mM Na₃VO₄, 1 mM PMSF (phenylmethylsulphonylfluoride), 2 mM 2-mercaptoethanol, 2 mM imidazole, 1 μg/ml aprotinin, 1μg/ml pepstatin, 1 pg/ml leupeptin), using 1.0 ml per 3×10⁷ cells. Lysiswas achieved using a dounce homogeniser, following which the lysate wascentrifuged at 41,000 g for 35 minutes. Aspirated supernatant was pumpedonto a 5 mm diameter chromatography column containing 500 μl Ni NTA(nitrilo-tri-acetic acid) agarose (Qiagen, product no. 30250) which hadbeen equilibrated in lysis buffer. A baseline level of UV absorbance forthe eluent was reached after washing the column with 12 ml of lysisbuffer followed by 7 ml of wash buffer (25 mM HEPES pH7.4 at 4° C., 100mM KCl, 20 mM imidazole, 2 mM 2-mercaptoethanol). Bound Aurora-A proteinwas eluted from the column using elution buffer (25 mM HEPES pH7.4 at 4°C., 100 mM KCl, 400 mM imidazole, 2 mM 2-mercaptoethanol). An elutionfraction (2.5 ml) corresponding to the peak in UV absorbance wascollected. The elution fraction, containing active Aurora-A kinase, wasdialysed exhaustively against dialysis buffer (25 mM HEPES pH7.4 at 4°C., 45% glycerol (v/v), 100 mM KCI, 0.25% Nonidet P40 (v/v), 1 mMdithiothreitol).

Each new batch of Aurora-A enzyme was titrated in the assay by dilutionwith enzyme diluent (25 mM Tris-HCl pH7.5, 12.5 mM KCl, 0.6 mM DTT). Fora typical batch, stock enzyme is diluted 1 in 666 with enzyme diluentand 20 μl of dilute enzyme is used for each assay well. Test compounds(at 10 mM in dimethylsulphoxide (DMSO) were diluted with water and 10 μlof diluted compound was transferred to wells in the assay plates.“Total” and “blank” control wells contained 2.5% DMSO instead ofcompound. Twenty microlitres of freshly diluted enzyme was added to allwells, apart from “blank” wells. Twenty microlitres of enzyme diluentwas added to “blank” wells. Twenty microlitres of reaction mix (25 mMTris-HCl, 78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM MnCl₂,6.25 mM ATP, 7.5 μM peptide substrate[biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) containing 0.2 μCi [γ³³P]ATP(Amersham Pharmacia, specific activity≧2500 Ci/mmol) was then added toall test wells to start the reaction. The plates were incubated at roomtemperature for 60 minutes. To stop the reaction 100 μl 20% v/vorthophosphoric acid was added to all wells. The peptide substrate wascaptured on positively-charged nitrocellulose P30 filtermat (Whatman)using a 96-well plate harvester (TomTek) and then assayed forincorporation of ³³P with a Beta plate counter. “Blank” (no enzyme) and“total” (no compound) control values were used to determine the dilutionrange of test compound which gave 50% inhibition of enzyme activity.

In this test, the compounds of the invention give 50% inhibition ofenzyme activity at concentrations of 0.3 nM to 1000 nM and in particularcompound 24 in Table 2 gave 50% inhibition of enzyme activity at aconcentration of 0.3 nM.

(b) In Vitro Aurora-B Kinase Inhibition Test

This assay determines the ability of a test compound to inhibitserine-threonine kinase activity. DNA encoding Aurora-B may be obtainedby total gene synthesis or by cloning. This DNA may then be expressed ina suitable expression system to obtain polypeptide with serine-threoninekinase activity. In the case of Aurora-B, the coding sequence wasisolated from cDNA by polymerase chain reaction (PCR) and cloned intothe pFastBac system in a manner similar to that described above forAurora-A (i.e. to direct expression of a 6-histidine tagged Aurora-Bprotein).

For the large scale expression of Aurora-B kinase activity, Sf21 insectcells were grown at 28° C. in TC100 medium supplemented with 10% foetalcalf serum (Viralex) and 0.2% F68 Pluronic (Sigma) on a Wheaton rollerrig at 3 r.p.m. When the cell density reached 1.2×10⁶ cells ml⁻¹ theywere infected with plaque-pure Aurora-B recombinant virus at amultiplicity of infection of 1 and harvested 48 hours later. Allsubsequent purification steps were performed at 4° C. Frozen insect cellpellets containing a total of 2.0×10⁸ cells were thawed and diluted withlysis buffer (50 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulphonic acid]) pH7.5 at 4°C., 1 mM Na₃VO₄, 1 mM PMSF (phenylmethylsulphonyl fluoride), 1 mMdithiothreitol, 1 μg/ml aprotinin, 1 μg/ml pepstatin, 1 μg/mlleupeptin), using 1.0 ml per 2×10⁷ cells. Lysis was achieved using asonication homogeniser, following which the lysate was centrifuged at41,000 g for 35 minutes. Aspirated supernatant was pumped onto a 5 mmdiameter chromatography column containing 1.0 ml CM sepharose Fast Flow(Amersham Pharmacia Biotech) which had been equilibrated in lysisbuffer. A baseline level of UV absorbance for the eluent was reachedafter washing the column with 12 ml of lysis buffer followed by 7 ml ofwash buffer (50 mM HEPES pH7.4 at 4° C., 1 mM dithiothreitol). BoundAurora-B B protein was eluted from the column using a gradient ofelution buffer (50 mM HEPES pH7.4 at 4° C., 0.6 M NaCl, 1 mMdithiothreitol, running from 0% elution buffer to 100% elutionbufferover 15 minutes at a flowrate of 0.5 m/min). Elution fractions (1.0 ml)corresponding to the peak in UV absorbance was collected. Elutionfractions were dialysed exhaustively against dialysis buffer (25 mMHEPES pH7.4 at 4° C., 45% glycerol (v/v), 100 mM KCl, 0.05% (v/v) IGEPALCA630 (Sigma Aldrich), 1 mM dithiothreitol). Dialysed fractions wereassayed for Aurora-B kinase activity.

Each new batch of Aurora-B enzyme was titrated in the assay by dilutionwith enzyme diluent (25 mM Tris-HCl pH7.5, 12.5 mM KCl, 0.6 mM DTT). Fora typical batch, stock enzyme is diluted 1 in 40 with enzyme diluent and20 μl of dilute enzyme is used for each assay well. Test compounds (at10 mM in dimethylsulphoxide (DMSO) were diluted with water and 10 μl ofdiluted compound was transferred to wells in the assay plates. “Total”and “blank” control wells contained 2.5% DMSO instead of compound.Twenty microlitres of freshly diluted enzyme was added to all wells,apart from “blank” wells. Twenty microlitres of enzyme diluent was addedto “blank” wells. Twenty microlitres of reaction mix (25 mM Tris-HCl,78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM MnCl₂, 37.5 mMATP, 25 μM peptide substrate [biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG])containing 0.2 μCi [γ³³P]ATP (Amersham Pharmacia, specific activity≧2500Ci/mmol) was then added to all test wells to start the reaction. Theplates were incubated at room temperature for 60 minutes. To stop thereaction 100 μl 20% v/v orthophosphoric acid was added to all wells. Thepeptide substrate was captured on positively-charged nitrocellulose P30filtermat (Whatman) using a 96-well plate harvester (TomTek) and thenassayed for incorporation of ³³P with a Beta plate counter. “Blank” (noenzyme) and “total” (no compound) control values were used to determinethe dilution range of test compound which gave 50% inhibition of enzymeactivity.

In this test, the compounds of the invention give 50% inhibition ofenzyme activity at concentrations of 0.3 nM to 1000 nM and in particularcompound 24 in Table 2 gave 50% inhibition of enzyme activity at aconcentration of 12.3 nM.

(c) In Vitro Cell Proliferation Assay

This and other assays can be used to determine the ability of a testcompound to inhibit the growth of adherent mammalian cell lines, forexample the human tumour cell line SW620 (ATCC CCL-227). This assaydetermines the ability of at test compound to inhibit the incorporationof the thymidine analogue, 5′-bromo-2′-deoxy-uridine (BrdlD intocellular DNA. SW620 or other adherent cells were typically seeded at1×10⁵ cells per well in L-15 media (GIBCO) plus 5% foetal calf serum, 1%L-glutamine (100 μl /well) in 96 well tissue culture treated 96 wellplates (Costar) and allowed to adhere overnight. The following day thecells were dosed with compound (diluted from 10 mM stock in DMSO usingL-15 (with 5% FCS, 1% L-glutamine). Untreated control wells and wellscontaining a compound known to give 100% inhibition of BrdUincorporation were included on each plate. After 48 hours in thepresence/absence of test compound the ability of the cells toincorporate BrdU over a 2 hour labelling period was determined using aBoelringer (Roche) Cell Proliferation BrdU ELISA kit (cat. No. 1 647229) according to manufacturers directions. Briefly, 15 μl of BrdUlabelling reagent (diluted 1:100 in media- L-15, 5% FCS, 1% L-glutamine)was added to each well and the plate returned to a humidified (+5% CO₂)37° C. incubator for 2 hours. After 2 hours the labelling reagent wasremoved by decanting and tapping the plate on a paper towel. FixDenatsolution (50 μl per well) was added and the plates incubated at roomtemperature for 45 minutes with shaking. The FixDenat solution wasremoved by decanting and tapping the inverted plate on a paper towel.The plate was then washed once with phosphate buffered saline (PBS) and100 μl /well of Anti-BrdU-POD antibody solution (diluted 1:100 inantibody dilution buffer) added. The plate was then incubated at roomtemperature with shaking for 90 minutes. Unbound Anti-BrdU-POD antibodywas removed by decanting and washing the plate 4 times with PBS beforebeing blotted dry. TMB substrate solution was added (100 μl/well) andincubated for approximately 10 minutes at room temperature with shakinguntil a colour change was apparent. The optical density of the wells wasthen determined at 690 nm wavelength using a Titertek Multiscan platereader. The values from compound treated, untreated and 100% inhibitioncontrols were used to determine the dilution range of a test compoundthat gave 50% inhibition of BrdU incorporation. The compounds of theinvention are active at 0.3 nM to 10000 nM in this test and inparticular compound 24 in table 2 was active at 300 nM.

(d) In Vitro Cell Cycle Analysis Assay

This assay determines the ability of a test compound to arrest cells inspecific phases of the cell cycle. Many different mammalian cell linescould be used in this assay and SW620 cells are included here as anexample. SW620 cells were seeded at 7×10⁵ cells per T25 flask (Costar)in 5 ml L-15 (5% FCS, 1% L-glutamine). Flasks were then incubatedovernight in a humidified 37° C. incubator with 5% CO₂. The followingday, 5 μl of L-15 (5% FCS, 1% L-glutamine) carrying the appropriateconcentration of test compound solubilised in DMSO was added to theflask. A no compound control treatments was also included (0.5% DMSO).The cells were then incubated for a defined time (24 hours) withcompound. After this time the media was aspirated from the cells andthey were washed with 5 ml of prewarmed (37° C.) sterile PBSA, thendetached from the flask by brief incubation with trypsin and followed byresuspension in 5 ml of 1% Bovine Serum Albumin (BSA, Sigma-Aldrich Co.)in sterile PBSA. The samples were then centrifuged at 2200 rpm for 10minutes. The supernatant was aspirated to leave 200 μl of the PBS/BSAsolution. The pellet was resuspended in this 200 μl of solution bypipetting 10 times to create a single cell suspension. One ml ofice-cold 80% ethanol was slowly added to each cell suspension and thesamples stored at −20° C. overnight or until required for staining.Cells were pelleted by centrifugation, ethanol aspirated off and pelletsresuspended in 200 μl PBS containing 100 μg/ml RNAse (Sigma Aldrich) and10 μg/ml Propidium Iodide (Sigma Aldrich). Cell suspensions wereincubated at 37° C. for 30 minutes, a further 200 μl PBS added andsamples stored in the dark at 4° C. overnight.

Each sample was then syringed 10 times using 21-guage needle. Thesamples were then transferred to LPS tubes and DNA content per cellanalysed by Fluorescence activated cell sorting (FACS) using a FACScanflow cytometer (Becton Dickinson). Typically 30,000 events were countedand recorded using CellQuest v1.1 software (Verity Software). Cell cycledistribution of the population was calculated using Modfit software(Verity Software) and expressed as percentage of cells with 2N (G0/G1),2N-4N (S phase) and with 4N (G2/M) DNA content.

The compounds of the invention are active in this test at 0.3 nM to10000 nM and in particular compounds 24 in table 2 was active at 1.5 μM

The invention will now be illustrated in the following non limitingexamples, in which standard techniques known to the skilled chemist andtechniques analogous to those described in these Examples may be usedwhere appropriate, and in which, unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and    work up procedures were carried out after removal of residual solids    such as drying agents by filtration;-   (ii) operations were carried out at ambient temperature, typically    in the range 18-25° C. and in air unless stated, or unless the    skilled person would otherwise operate under an atmosphere of an    inert gas such as argon;-   (iii) column chromatography (by the flash procedure) and medium    pressure liquid chromatography (MPLC) were performed on Merck    Kieselgel silica (Art. 9385);-   (iv) yields are given for illustration only and are not necessarily    the maximum attainable;-   (v) the structures of the end products of the formula (I) were    generally confirmed by nuclear (generally proton) magnetic resonance    (NMR) and mass spectral techniques; proton magnetic resonance    chemical shift values were measured in deuterated dimethyl    sulphoxide (DMSO d₆) (unless otherwise stated) on the delta scale    (ppm downfield from tetramethylsilane) using one of the following    four instruments    -   Varian Gemini 2000 spectrometer operating at a field strength of        300 MHz    -   Bruker DPX300 spectrometer operating at a field strength of 300        MHz    -   JEOL EX 400 spectrometer operating at a field strength of 400        MHz    -   Bruker Avance 500 spectrometer operating at a field strength of        500 MHz-   Peak multiplicities are shown as follows: s, singlet; d, doublet;    dd, double doublet; t, triplet; q, quartet; qu, quintet; m,    multiplet; br s, broad singlet.-   (vi) robotic synthesis was carried out using a Zymate XP robot, with    solution additions via a Zymate Master Laboratory Station and    stirred via a Stem RS5000 Reacto-Station at 25° C.;-   (vii) work up and purification of reaction mixtures from robotic    synthesis was carried out as follows: evaporations were carried out    in? vacuo using a Genevac HT 4; column chromatography was performed    using either an Anachem Sympur MPLC system on silica using 27 mm    diameter columns filled with Merck silica (60 μm, 25 g); the    structures of the final products were confirmed by LCMS on a Waters    2890/ZMD micromass system using the following and are quoted as    retention time (RT) in minutes:-   Column: waters symmetry C18 3.5 μm 4.6×50 mm-   Solvent A: H₂O-   Solvent B: CH₃CN-   Solvent C: methanol+5% HCOOH-   Flow rate: 2.5 ml/min-   Run time: 5 minutes with a 4.5 minute gradient from 0-100% C-   Wavelength: 254 nm, bandwidth 10 nm-   Mass detector: ZMD micromass-   Injection volume 0.005 ml-   (viii) Analytical LCMS for compounds which had not been prepared by    robotic synthesis was performed on a Waters Alliance HT system using    the following and are quoted as retention time (RT) in minutes:-   Column: 2.0 mm×5 cm Phenomenex Max-RP 80A-   Solvent A: Water-   Solvent B: Acetonitrile-   Solvent C: Methanol/1% formic acid or Water/1% formic acid-   Flow rate: 1.1 ml/min-   Run time: 5 minutes with a 4.5 minute gradient from 0-95% B+constant    5% solvent C-   Wavelength: 254 nm, bandwidth 10 nm-   Injection volume 0.005 ml-   Mass detector: Micromass ZMD-   (ix) Preparative high performance liquid chromatography (HPLC) was    performed on either—Waters preparative LCMS instrument, with    retention time (RT) measured in minutes:-   Column: β-basic Hypercil (21×100 mm) 5 μm-   Solvent A: Water/0.1% Ammonium carbonate-   Solvent B: Acetonitrile-   Flow rate: 25 ml/min-   Run time: 10 minutes with a7.5 minute gradient from 0-100% B-   Wavelength: 254 nm, bandwidth 10 nm-   Injection volume 1-1.5 ml-   Mass detector: Micromass ZMD-   Gilson preparative HPLC instrument, with retention time (RT)    measured in minutes:-   Column: 21 mm×15 cm Phenomenex Luna2 C18-   Solvent A: Water+0.1% trifluoracetic acid,-   Solvent B: Acetonitrile+0.1% trifluoracetic acid-   Flow rate: 21 ml/min-   Run time: 20 minutes with various 10 minute gradients from 5-100% B-   Wavelength: 254 nm, bandwidth 10 nm-   Injection volume 0.1-4.0 ml-   (x) intermediates were not generally fully characterised and purity    was assessed by thin layer chromatography (TLC), HPLC, infra-red    (IR), MS or NMR analysis.

Particular examples of compounds of formula (I) are set out in Tables 1,2 and 3: TABLE 1

Compound R1 R2 1

OCH₂—(3-chlorophenyl) 2

NH—CO—(3-chlorophenyl) 3

NH—CO—(3-chlorophenyl) 4

NH—CO—(3-chlorophenyl) 5

NH—CO—(3-chlorophenyl) 6

NH—CO—(3-chlorophenyl) 7

NH—CO—(3-fluorophenyl) 8

NH—CO—(3,4-difluorophenyl) 9

NH—CO—(3-chlorophenyl) 10

NH—CO—(3-chlorophenyl) 11

NH—CO—(3-chlorophenyl) 12

NH—CO—(3-chlorophenyl) 13

NH—CO—(3-chlorophenyl) 14

NH—CO—(3-chlorophenyl) 15

NH—CO—(3-fluorophenyl) 16

NH—CO—(3-chlorophenyl) 17

NH—CO—(3-chlorophenyl) 18

NH—CO—(3-chlorophenyl) 19

NH—CO—(3-chlorophenyl) 20

NH—CO—(3-chlorophenyl) 21

NH—CO—(3-chlorophenyl) 22

NH—CO—(3-chlorophenyl)

TABLE 2

R1 R2 23

NH—CO—(3-chloro,4-fluorophenyl) 24

NH—CO—(3-chloro-4-fluorophenyl) 25

NH—CO—(3-chlorophenyl) 26

CH₂NH—(3-chloro-4-fluorophenyl) 27

OCH₂—(3-chloro-4-fluorophenyl) 28

NH—CO—(3-chlorophenyl)

TABLE 3

Compound R1 R2 29

NH—CO—(3-chloro-4-fluorophenyl) 30

NH—CO—(3-chloro-4-fluorophenyl)

EXAMPLE 1 Preparation of Compound 1 in Table1-3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyldihydrogen phosphate

3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutan-1-ol(1.7 g, 3.1 mmol) and dry 1H-tetrazole (647 mg, 9.23 mmol) weredissolved with heating (50° C.) in dry dimethylacetamide (8 ml) under anitrogen atmosphere. Di-tert-butyl-N,N-diethylphosphoramidite (1.2 ml,4.3 mmol) was added dropwise to the reaction mixture and left to stir atambient temperature for 20 hours.

The reaction mixture was diluted with dichloromethane (160 ml) andwashed with aqueous sodium bicarbonate solution (50 ml of a saturatedsolution). The aqueous layer was father extracted with dichloromethane(150 ml) and the combined organics were dried (sodium sulphate),filtered and concentrated under reduced pressure to yield di-tert-butyl3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutylphosphite as a viscous, yellow oil. The oil was dissolved intetrahydrofuran (10 ml) and hydrogen peroxide (680 μl of a 30% w/waqueous solution, 8.8 N, 6.00 mmol) was added slowly at 0° C. Thereaction was warmed to ambient temperature over 10 minutes. Theresulting homogeneous solution was stirred for 2 hours then cooled to 0°C. and a solution of sodium metabisulphite (11.5 ml of a 0.53 N aqueoussolution) was introduced dropwise. The reaction was warmed to ambienttemperature over 15 minutes then diluted with ethyl acetate (100 ml).Aqueous sodium bicarbonate solution (100 ml of a saturated aqueoussolution) was added, the phases separated and the aqueous layer furtherextracted with ethyl acetate (3×100 ml). The combined organics weredried (sodium sulphate), filtered and concentrated under reducedpressure to yield di-tert-butyl3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutylphosphate as a viscous, yellow oil (1.97 g), which was used in the nextstep of the reaction sequence without further purification.

³¹P-NMR {¹H}(CDCl₃): −8.73 (s, 1P):

MS (+ve ESI): 744 (M+H)⁺.

Hydrogen chloride (4.30 ml of a 4.0 N solution in 1,4-dioxane, 17.2mmol) was added, dropwise to a solution of the crude phosphate ester(1.97 g) in 1,4-dioxane (86 ml) upon which a white solid precipitatedfrom the reaction mixture. The resulting heterogeneous reaction mixturewas stirred for a further 19 hours and diethyl ether was added (100 ml).The precipitate was filtered and washed with diethyl ether (3×30 ml)then dried under high vacuum for 48 hours to yield the title compound,3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyldihydrogen phosphate (di-hydrochloride salt) as an off-white solid (1.7g, 91% yield):

¹H-NMR (DMSO-d₆): 11.86 (s, 1H), 9.12 (br s, 2H), 8.81 (s, 1H), 8.53 (s,1H), 8.50 (d, 1H), 8.08 (dd, 1H), 7.54 (br s, 1H), 7.46-7.39 (m, 4H),7.05 (d, 1H), 5.41 (s, 2H), 4.34 (t, 2H), 4.05 (s, 3H), 3.98 (dd, 2H),3.11 (br s, 2H), 2.30 (m, 2H), 2.05 (t, 2H), 1.36 (s, 6H):

³¹P-NMR {¹H}(DMSO-d₆): −0.05 (s, 1P):

MS (−ve ESI): 630 (M−H)⁻,

MS (+ve ESI): 632 (M+H)⁺.

3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutan-1-ol,used as the starting material, was obtained as follows:

5 a) A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04mol), (prepared according to J. Med. Chem. 1977, 20, 146-149), andGold's reagent (7.4 g, 0.05 mol) in dioxane (100 ml) was stirred andheated at reflux for 24 hours. Sodium acetate (3.02 g, 0.04 mol) andacetic acid (1.65 ml, 0.03 mol) were added to the reaction mixture andit was heated for a further 3 hours. The volatiles were removed byevaporation and water was added to the residue. The solid was collectedby filtration, washed with water and dried. Recrystallisation fromacetic acid yielded 7-(benizyloxy)-6-methoxyquinazolin-4(3H)-one (8.7 g,84% yield) as a white solid.

b) Chloromethyl pivalate (225 ml, 1.56 mol) was added dropwise to astirred mixture of 7-(benzyloxy)-6-methoxyquinazolin-4(3H)-one (400 g,1.42 mol) and potassium carbonate (783 g, 5.67 mol) indiimethylacetamide (5500 ml). The reaction was heated to 90 ° C. for 4hours. The reaction was cooled and filtered to remove inorganic salts.The filtrate was concentrated in vacuo to yield, crude[7-(benzyloxy)-6-methoxy-4-oxoquinazolin-3(4H)-yl]methyl pivalate (562g, 100% yield):

¹H-NMR (DMSO-d₆): 8.33 (s, 1H), 7.30-7.50 (m, 6H), 7.25 (s, 1H), 5.90(s, 2H), 5.25 (s, 2H), 3.88 (s, 3H), 1.10 (s, 9H):

MS (+ve ESI): 397 (M+H)⁺.

c) 10% palladium on carbon (56 g, 53 mmol) was added to a solution of[7-(benzyloxy)-6-methoxy-4-oxoquinazolin-3(4H)-yl]methyl pivalate (562g, 1.42 mmol) in dimethylacetamide (3500 ml) at ambient temperature andstirred for 3 hours under an atmosphere of hydrogen (1 bar). Thereaction was filtered through a pad of celite and the solvent evaporatedin vacuo. The residual solid was dissolved in 20% methanol indichloromethane and passed through a pad of silica gel. Evaporation ofthe solvent in vacuo followed by trituration with methanol yielded,(7-hydroxy-6-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (188 g,43% yield):

¹H-NMR (DMSO-d₆): 8.25 (s, 1H), 7.45 (s, 1H), 6.97 (s, 1H), 5.85 (s,2H), 4.04 (s, 1H), 3.87 (s, 3H), 1.10 (s, 9H):

MS (+ve ESI): 307 (M+H)⁺.

d) A mixture of (7-hydroxy-6-methoxy-4-oxoquinazolin-3(4,1)-yl)methylpivalate (100 g, 0.33 mol), 3-bromopropanol (49.3 g, 0.35 mol) andpotassium carbonate (133 g, 0.96 mol) in dimethylformamide (500 ml) wasstirred at 80° C. for 20 hours. The reaction was cooled and concentratedto quarter volume in vacuo. The residue was poured into ice/water (1500ml) and the resulting solid collected by suction filtration.Purification by crystallisation from ethanol, yielded7-(3-hydroxypropoxy)-6-methoxy-4-oxoquinazolin-3(4H)-yl methyl pivalate(33.8 g, 41% yield) as a beige solid:

¹H-NMR (DMSO-d₆): 7.95 (s, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 4.16 (t,2H), 3.86 (m, 5H), 2.08 (t, 2H), 1.12 (s, 9H):

MS (+ve ESI): 365 (M+H)⁺.

e) An aqueous sodium hydroxide solution (100 ml, 0.20 mol) was added toa solution of yielded7-(3-hydroxypropoxy)-6-methoxy-4-oxoquinazolin-3(4H)-yl methyl pivalate(33.8 g, 93.0 mmol) in methanol (300 ml) and the solution heated toreflux for 1 hour. The methanol was evaporated in vacuo, the residue wasacidified with aqueous hydrochloric acid, sodium bicarbonate was addedand the solid was collected by suction filtration. Washing with waterand drying yielded 7-(3-hydroxypropoxy)-6-methoxyquinazolin-4(3H)-one(26 g, 95% yield):

¹H-NMR (DMSO-d₆): 7.96 (s, 1H), 7.41 (s, 1H), 7.07 (s, 1H), 4.14 (t,2H), 3.84 (s, 3H), 3.55 (t, 2H), 1.90 (t, 2H):

MS (+ve ESI): 251 (M+H)⁺.

f) 7-(3-hydroxypropoxy)-6-methoxyquinazolin-4(3H)-one (25.0 g, 100 mmol)was added slowly to a solution of dimethylformamide (1 ml) in thionylchloride (250 ml). The mixture was heated to reflux for 4 hours thencooled and the solvents evaporated in vacuo. The residue was dissolvedin dichloromethane and washed with aqueous sodium bicarbonate, brine,dried over magnesium sulphate and evaporated. Trituration and collectionof the solid by suction filtration yielded4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline (19.5 g, 68% yield) asa yellow solid:

¹H-NMR (CDCl₃): 8.85 (s, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 4.38 (t, 2H),4.03 (s, 3H), 3.8 (t, 2H), 2.40 (m, 2H):

MS (+ve ESI): 287 (M+H)⁺.

g) 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline (574 mg, 2.00 mmol)and 5-amino-2-(3-chlorobenzyloxy)pyridine (468 mg, 2.0 mmol, see WO0121597) were heated in dimethylacetamide (10 ml) at 100° C. for 4hours. The reaction was cooled to ambient temperature and the solidcollected by suction filtration and washed with diethyl ether (25 ml)and acetone (5 ml). Drying in vacuo yieldedN-{6-[(3-chlorobenzyl)oxy]pyridin-3-yl}-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine(640 mg, 66% yield) as a white solid:

¹H-NMR (DMSO-d₆): 11.60 (s, 1H), 8.78 (s, 1H), 8.46 (s, 1H), 8.37 (s,1H), 8.04.(dd, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.03 (d, 1H), 5.39 (s,2H), 4.29 (t, 2H), 4.01 (s, 3H), 3.82 (t, 2H), 2.29 (m, 2H):

MS (+ve ESI): 485.5 (M+H)⁺.

h)N-{6-[(3-chlorobenzyl)oxy]pyridin-3-yl}-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine(1.83 g, 3.77 mmol), 3-amino-3-methylbutanol (1.94 g, 18.9 mmol) andpotassium iodide (62 mg, 0.38 mmol) in dimethylacetamide (10 ml) washeated at 90° C. for 16 hours. The mixture was cooled, poured into 2.0 Naqueous ammonia (150 ml) and the supernatant decanted off and extractedwith ethyl acetate (2×50ml). The insoluble gum was dissolved indichloromethane/methanol mixture, combined with the ethyl acetatefraction and evaporated in vacuo. Purification by flash chromatographyon silica gel, eluting with dichloromethane: methanol: aqueous ammonia(100:5:0.3 to 100:25:2) yielded3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutan-1-ol(1.56 g, 75% yield) as an off-white solid:

¹H-NMR (DMSO-d₆): 9.52 (s, 1H), 8.40 (m 2H), 8.09 (dd, 1H), 7.80 (s,1H), 7.53 (s, 1H), 7.41 (m, 3H), 7.18 (s, 1H), 6.97 (d, 1H), 5.38 (s,2H), 4.19 (t, 1H), 3.96 (s, 3H), 3.52 (t, 2H), 2.64 (t, 2H), 1.88 (t,2H), 1.51 (t, 2H), 1.03 (s, 6H):

MS (−ve ESI): 550.7 (M−H)⁻,

MS (+ve ESI): 552.7 (M+H)⁺.

EXAMPLE 2 Preparation of Compound 2 in Table 1-3-[(3-{[4-({6-[(3chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7yl]oxy}propyl)amino]-3-methylbutyl dihydroen phosphate

Di-tert-butyl-N,N-diethylphosphoramidite (660 mg, 2.65 mmol) was addedslowly to a mixture of3-chloro-N-{5-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]propoxy}-6-methoxquinazolin-4-yl)amino]pyridin-2-yl}benzamide(742 mg, 1.31 mmol) and 1H-tetrazole (273 mg, 3.9 mmol) indimethylacetamide (1.7 ml). The reaction was stirred under an inertatmosphere at ambient temperature for 24 hours during which a furtherportion of di-tert-butyl-N,N-diethylphosphoramidite (330 mg, 1.32 mmol)was added. Dichloromethane (34 ml), methanol (1.7 ml) and 20% aqueouspotassium hydrogen carbonate solution (5 ml) were added and the reactionmixture stirred briefly. The aqueous layer was removed by filtrationthrough a Varian CE1020 Chem Elut Hydromatrix cartridge. Solventevaporation in vacuo gave a yellow oil which was taken up intetrahydrofuran (2 ml), cooled to 0° C. and treated with 30% aqueoushydrogen peroxide (0.4 ml, 3.9 mmol). The mixture was allowed to warm toambient temperature and stirred for 2 hours. The reaction was cooled to0° C., quenched with aqueous sodium metabisulphite, treated with 20%aqueous potassium hydrogen carbonate and extracted into 10:1dichloromethane: methanol (4×10 ml). Solvent evaporation in vacuo gave ayellow oil, which was taken up in dioxane (40 ml) and treated dropwisewith a 4.0 N solution of hydrogen chloride in dioxane (1.96 ml, 7.86mmol). The white slurry was stirred at ambient temperature for 18 hours,diluted with an equal volume of dichloromethane and the solutionabsorbed onto flash silica. Purification by flash chromatography,eluting with dichloromethane : methanol: formic acid: water (100:20:3:3to 100:40:10:10), yielded the title compound (as the trihydrochloridesalt, 380 mg, 38% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆+CD₃COOD): 8.80 (s, 1H), 8.73 (d, 1H), 8.30 (m, 2H), 8.19(dd, 1H), 8.04 (m, 1H), 7.96 (d, 1H), 7.60 (m, 1H), 7.50 (t, 1H), 7.39(s, 1H), 4.31 (t, 2H), 4.02 (m, 5H), 3.11 (t, 2H), 2.27 (m, 2H), 2.04(m, 2H), 1.35 (s, 6H):

³¹P-NMR (DMSO-d₆+CD₃COOD): 0.08 (s, 1P):

MS (+ve ESI): 645.7, 647.7 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) 3-chlorobenzoyl chloride (22.1 g, 127 mmol) was added dropwise to astirred solution of 2-amino-5-nitropyridine (16.0 g, 115 mmol) inpyridine (240 ml) and heated to 100° C. for 16 hours. The solution wasevaporated in vacuo, the resulting solid was taken-up in dichloromethane(200 ml) and eluted through silica gel (800 g), with dichloromethane.The relevant fractions were combined and concentrated under reducedpressure to yield 3-chloro-N-(5-nitropyridin-2-yl)benzamide (31.6 g, 99%yield) as an off-white solid:

¹H-NMR (DMSO-d₆): 11.64 (s, 1H), 9.20 (d, 1H), 8.63 (dd, 1H), 8.40 (d,1H), 8.06 (s, 1H),

7.98 (d, 1H), 7.69 (d, 1H), 7.55 (dd, 1H):

MS (−ve ESI): 276 (M−H)⁻,

MS (+ve ESI): 278 (M+H)⁺.

b) 3-Chloro-N-(5-nitropyridin-2-yl)benzamide (31.5 g, 113 mmol) and 10%platinum on carbon (3.6 g) in dichloromethane was stirred under ahydrogen atmosphere (1 bar pressure) for 18 hours. The suspension wasfiltered through Celite®, the filter calke was washed with ethylacetate: ethanol (10:1, 1400 ml) and the filtrate concentrated underreduced pressure to yield N-(5-aminopyridin-2-yl)-3-chlorobenzamide(26.3 g, 94% yield) as an off-white powdery solid:

¹H-NMR (DMSO-d₆): 10.50 (s, 1H), 8.03 (s, 1H), 7.96 (d, 1H), 7.80 (d,1H), 7.76 (d, 1H), 7.61 (d, 1H), 7.52 (dd, 1H), 7.04 (dd, 1H), 5.22 (s,2H):

MS (−ve ESI): 246 (M−H)⁻,

MS (+ve ESI): 248 (N+H)⁺.

c) 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline (2.87 g, 10.0 mmol)and N-(5-aminopyridin-2-yl)-3-chlorobenzamide (2.54 g, 10.0 mmol) weresuspended in dry dimethylacetamide (100 ml) under a nitrogen atmosphereand warmed to 50° C. Hydrogen chloride (2.5 ml of a 4.0 N solution in1,4-dioxane, 10 mmol) was added dropwise, causing precipitation of ayellow solid from the reaction mixture. The resulting heterogeneousreaction mixture was stirred for 4.5 hours at 80° C. then cooled toambient temperature. Diethyl ether (200 ml) was added and the solidcollected by suction filtration to yield3-chloro-N-(5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamidehydrochloride as a pale yellow solid (4.83 g, 90% yield):

¹H-NMR (DMSO-d₆): 11.64 (br s, 1H), 11.04 (br s, 1H), 8.83 (s, 1H), 8.75(d, 1H), 8.39 (s, 1H), 8.25 (d, 1H), 8.18 (dd, 1H), 8.08 (s, 1H), 7.97(d, 1H), 7.65 (d, 1H), 7.55 (t, 1H), 7.39 (s, 1H), 4.30 (t, 2H), 4.03(s, 3H), 3.82 (t, 2H), 2.29 (m, 2H):

MS (−ve ESI): 496.3 (M−H)⁻,

MS (+ve ESI): 498.3 (M+H)⁺.

d)3-chloro-N-(5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamidehydrochloride (1.07 g, 2.00 mmol), 3-amino-3-methylbutanol (1.03 g, 10.0mmol) and potassium iodide (32 mg, 0.2 mmol) in dimethylacetamide (2.5ml) was heated at 80° C. for 4 days. The mixture was cooled, dilutedwith dichloromethane (25 ml) and the solution absorbed onto silica gel.Purification by flash chromatography, eluting with dichloromethane:methanol: aqueous ammonia (100:5:0.5 to 100:25:2), yielded3-chloro-N-{5-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamideas a pale yellow solid (804 mg, 71% yield):

¹H-NMR (DMSO-d₆): 10.92 (br s, 1H), 9.68 (s, 1H), 8.80 (s, 1H), 8.48 (s,1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.08 (s, 1H), 8.00 (d, 1H), 7.88 (s,1H), 7.66 (d, 1H), 7.55 (dd, 1H), 7.20 (s, 1H), 4.20 (t, 2H), 3.97 (s,3H), 3.50 (m, 2H), 2.74 (t, 2H), 1.94 (m, 2H), 1.57 (m, 2H), 1.07 (s,6H):

MS (−ve ESI): 563 (M−H)⁻,

MS (+ve ESI): 565 (M+H)⁺.

EXAMPLE 3 Preparation of Compound 3 in Table 1-2-[(3-{[4-({6-[(3chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]ethyldihydrogen phosphate

An analogous reaction to that described in example 2, but starting with3-chloro-N-{5-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(244 mg, 0.443 mmol), yielded the title compound (as thetrihydrochloride salt, 174 mg, 53% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆+CD₃COOD): 8.79 (s, 1H), 8.71 (d, 1H), 8.31 (d, 1H), 8.16(dd, 1H), 8.08 (s, 2H), 8.00 (d, 1H), 7.63 (m, 1H), 7.53 (m, 2H), 4.41(t, 2H), 4.20 (m, 2H), 4.02 (s, 3H), 3.41 (m, 2H), 3.32 (t, 2H), 3.26(q, 2H), 2.24 (m, 2H), 1.28 (t, 3H):

MS (+ve ESI): 631.6, 633.6 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as described in example 2dbut starting with 2-(ethylamino)ethanol (334 mg, 3.75 mmol). Thereaction yielded3-chloro-N-{5-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(304 mg, 74% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 9.59 (s, 1H), 8.77 (d, 1H), 8.45 (s, 1H), 8.26 (dd,1H), 8.18 (d, 1H), 8.07 (t, 1H), 7.98 (d, 1H), 7.81 (s, 1H), 7.65 (m,1H), 7.54 (t, 1H), 7.18 (s, 1H), 4.26 (t, 1H), 4.17 (t, 2H), 3.96 (s,3H), 3.42 (q, 2H), 2.58 (t, 2H), 2.50 (m, 4H), 1.98 (m, 2H), 0.95 (t,3H):

MS (+ve ESI): 551.5 (M+H)⁺.

MS (+ve ESI): 551.5 (M+H)⁺.

EXAMPLE 4 Preparation of Compound 4 in Table1-2-[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7yl]oxy}propyl)piperidin-2-yl]ethyl dihydrogen Phosphate

An analogous reaction to that described in example 2, but starting with3-chloro-N-{5-[(7-{3-[2-(2-hydroxyethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(286 mg, 0.48 mmol), yielded the title compound (as the trihydrochloridesalt, 114 mg, 31% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆+CD₃COOD): 8.92 (s, 1H), 8.71 (d, 1H), 8.31 (d, 1H), 8.17(m, 1H), 8.09 (s, 1H), 7.98 (d, 1H), 7.63 (m, 1H), 7.52 (m, 1H), 7.36(s, 1H), 4.32 (t, 2H), 4.03 (s, 3H), 3.96 (m, 2H), 3.30 (m, 5H), 2.30(m, 2H), 1.95 (m, 4H), 1.74 (m, 4H), 1.52 (m 2H):

MS (+ve ESI): 671.7, 673.7 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[2-(2-hydroxyethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as described in example 2dbut starting with 2-(hydroxyethyl)piperidine (1.29 g, 10.0 mmol). Thereaction yielded3-chloro-N-{5-[(7-{3-[2-(2-hydroxyethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(913 mg, 77% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 10.91 (s, 1H), 9.72 (br s, 1H), 8.81 (d, 1H), 8.46 (s,1H), 8.29 (dd, 1H), 8.20 (d, 1H), 8.10 (t, 1H), 8.00 (d, 1H), 7.91 (s,1H), 7.65 (m, 1H), 7.55 (t, 1H), 7.20 (s, 1H), 4.20 (t, 2H), 3.99 (s,3H), 3.50 (m, 2H), 3.00 (m, 2H), 2.80 (m, 2H), 2.60 (m, 1H), 2.03 (m,2H), 1.93 (m, 1H), 1.72 (m, 1H), 1.57 (m, 4H), 1.39 (m, 2H):

MS (−ve ESI): 589.6 (M−H)⁻,

MS (+ve ESI): 591.5 (M+H)⁺.

EXAMPLE 5 Preparation of Compound 5 in Table1-[(2R)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)pyrrolidin-2-yl]methyldihydrogen phosphate

An analogous reaction to that described in example 2, but starting with3-chloro-N-{5-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(78 mg, 0.139 mmol), yielded the title compound (as the trihydrochloridesalt, 49 mg, 47% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆+CD₃COOD): 8.85 (s, 1H), 8.74 (m, 1H), 8.32 (d, 1H), 8.21(m, 2H), 8.09 (s, 2H), 7.99 (d, 1H), 7.66 (m, 1H), 7.55 (t, 1H), 7.44(s, 1H), 4.35 (m, 2H), 4.21 (m, 1H), 4.12 (m, 1H), 4.04 (s, 3H), 3.80(m, 1H), 3.65 (m, 1H), 3.50 (m, 1H), 3.28 (m, 2H), 2.32 (m, 2H), 2.19(m, 1H), 1.95 (m, 3H):

MS (+ve ESI): 643.6, 645.6 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamideused as the starting material was obtained as follows:

A mixture of3-chloro-N-(5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamide(100 mg, 0.20 mmol), (2R)-pyrrolidin-2-ylmethanol (102 mg, 1.00 mmol)and tetra-n-butylammonium iodide (7.5 mg, 0.02 mmol) indimethylacetamide (1 ml) was heated at 60° C. for 17 hours. The mixturewas cooled and diluted with dichloromethane (10 ml) and purified byflash chromatography on silica gel, eluting withdichloromethane:methanol:7.0 N ammonia in methanol (9: 1:0 to 9:1:0.8)yielded3-chloro-N-{5-[(7-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(107 mg, 95% yield) as a yellow solid:

¹H-NMR (DMSO-d₆): 10.96 (s, 1H), 9.76 (s, 1H), 8.82 (d, 1H), 8.48 (s,1H), 8.30 (dd, 1H), 8.21 (d, 1H), 8.10 (s, 1H), 8.00 (d, 1H), 7.94 (s,1H), 7.67 (d, 1H), 7.55 (dd, 1H), 7.21 (s, 1H), 4.20 (t, 2H), 3.98 (s,3H), 3.48 (m, 2H), 2.73 (m, 2H), 1.55-2.15 (m, 7H):

MS (−ve ESI): 561.5 (M−H)⁻,

MS (+ve ESI): 563.6 (M+H)⁺.

EXAMPLE 6 Preparation of Compound 6 in Table1-2-[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperldin-4-yl]ethyldihydrogen phosphate

An analogous reaction to that described in example 2, but starting with3-chloro-N-{5-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(200 mg, 0.34 mmol), yielded the title compound (as the trihydrochloridesalt, 137 mg, 45% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆+CD₃COOD): 8.82 (s, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 8.27(m, 2H), 8.06 (s, 1H), 7.98 (d, 1H), 7.62 (m, 1H), 7.50 (m, 1H), 7.37(s, 1H), 4.29 (m, 2H), 4.02 (s, 3H), 3.90 (q, 2H), 3.53 (d, 2H), 3.22(m, 3H), 2.93 (t, 2H), 2.31 (m, 2H), 1.90 (m, 2H), 1.70 (m, 1H), 1.55(m, 3H):

MS (+ve ESI): 671.7, 673.7 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamideused as the starting material, was obtained as described in example 2dbut starting with 2-(piperidin-4-yl)ethanol (1.73 ml, 20.0 mmol). Thereaction yielded3-chloro-N-{5-[(7-{3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(1.4 g, 59% yield) as a yellow solid:

¹H-NMR (DMSO-d₆): 10.96 (br s, 1H), 9.61 (s, 1H), 8.79 (br s, 1H), 8.48(s, 1H), 8.30 (m, 1H), 8.21 (d, 1H), 8.10 (s, 1H), 8.00 (d, 1H), 7.84(s, 1H), 7.64 (d, 1H), 7.58 (m, 1H), 7.21 (s, 1H), 4.30 (m, 2H), 4.19(m, 2H), 3.98 (s, 3H), 3.48 (m, 2H), 2.73 (m, 2H) 2.41 (m, 2H),1.98-1.80 (m, 3H), 1.60 (d, 2H), 1.45 (br s, 2H), 1.05-1.20 (m, 2H):

MS (−ve ESI): 589.5 (M−H)⁻,

MS (+ve ESI): 591.5 (M+H)⁺.

EXAMPLE 7 Preparation of Compound 7 in Table1-2-[ethyl(3-{[4-({6-[(3-fluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]ethyldihydrogen phosphate

Di-tert-butyl-N,N-diethylphosphoramidite (630 mg, 2.52 mmol) was addedto a mixture of3-fluoro-N-{5-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(673 mg, 1.26 mmol) and dry 1 H-tetrazole (176 mg, 2.52 mmol) indimethylacetamide (10 ml). The reaction was stirred under an inertatmosphere at ambient temperature for 160 minutes. Dichloromethane (100ml) and 20% aqueous potassium hydrogen carbonate solution (5 ml) wereadded and the reaction mixture stirred briefly. The aqueous layer wasremoved by filtration through a Varian CE1020 Chem Elut Hydromatrixcartridge and the organic fraction was evaporated in vacuo to give ayellow oil which was taken up in tetrahydrofuran (5 ml). The solutionwas cooled to −5° C., 30% aqueous hydrogen peroxide (0.21 ml, 1.89 mmol)was added slowly and the reaction was stirred at 0° C. for 1 hour. Thereaction was washed with aqueous sodium metabisulphite and 20% aqueouspotassium hydrogen carbonate solution and extracted intodichloromethane. Solvent evaporation in vacuo gave a yellow oil whichwas purified by chromatography on silica gel, eluting withdichloromethane: methanol: concentrated aqueous ammonia (200:16: 1) toyield a pale yellow oil. This was taken up in dioxane (20 ml) andtreated dropwise with a 4.0 N solution of hydrogen chloride in dioxane(1.89 ml, 7.56 mmol). The white slurry was stirred at ambienttemperature for 18 hours, diluted with methanol (40 ml) anddichloromethane (40 ml) and the solution absorbed onto flash silica.Purification by flash chromatography, eluting withdichloromethane:methanol:formic acid:water (100:20:3:3 to 100:40:10:10),yielded the title compound (as the trihydrochloride salt, 324 mg, 37%yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆+CD₃COOD): 8.82 (d, 1H), 8.58 (s, 1H), 8.30 (dd, 2H),8.20 (d, 1H), 7.92 (s, 1H), 7.88 (d, 1H), 7.83 (d, 1H), 7.53 (dd, 1H),7.39 (m, 1H), 4.24 (t, 2H), 4.08 (m, 2H), 3.99 (s, 3H), 3.26 (m, 6H),2.24 (m, 2H), 1.25 (t, 3H):

³¹P-NMR (DMSO-d₆+CD₃COOD): 1.68 (s, 1P):

MS (+ve ESI): 615.5 (+H)⁺.

3-fluoro-N-{5-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 2a but startingwith 3-fluorobenzoyl chloride (4.95g, 31.2mmol) yieldedN-(5-nitropyridin-2-yl)-3-fluorobenzamide as a light yellow solid (6.44g, 88% yield):

¹H-NMR (DMSO-d₆): 11.58 (br s, 1H), 9.21 (s, 1H), 8.64 (dd, 1H), 8.42(d, 1H), 7.87 (m, 2H), 7.58 (m, 1H), 7.46 (m, 2H):

MS (−ve ESI): 260 (M−H)⁻,

MS (+ve ESI): 262 (M+H)⁺.

b) An analogous reaction to that described in example 2b but startingwith N-(5-nitropyridin-2-yl)-3-fluorobenzamide (5.8 g, 22.2 mmol)yielded N-(5-aminopyridin-2-yl)-3-fluorobenzamide as a cream solid (5.0g, 96% yield):

¹H-NMR (DMSO-d₆): 10.38 (br s, 1H), 7.79 (m, 4H), 7.55 (m, 1H), 7.38 (t,1H), 7.01 (dd, 1H), 5.18 (br s, 2H):

MS (−ve ESI): 230 (M−H)⁻,

MS (+ve ESI): 232 (M+H)⁺.

c) An analogous reaction to that described in example 2c but startingwith N-(5-aminopyridin-2-yl)-3-fluorobenzamide (0.69 g, 3.0 mmol)yielded3-fluoro-N-(5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamidehydrochloride as a pale yellow solid (1.52 g, 98% yield):

¹H-NMR (DMSO-d₆): 11.78 (br s, 1H), 11.02 (br s, 1H), 8.84 (s, 1H), 8.76(d, 1H), 8.45 (s, 1H), 8.21 (m, 2H), 7.86 (m, 2H), 7.55 (m, 1H), 7.43(m, 2H), 4.28 (t, 2H), 4.03 (s, 3H), 3.81 (t, 2H), 2.28 (m, 2H):

MS (−ve ESI): 480.0 (M−H)⁻,

MS (+ve ESI): 482.0 (M+H)⁺.

d) An anlogous reaction to that described in example 2d but startingwith3-fluoro-N-(5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamidehydrochloride (1.03 g, 2.00 mmol) and 2-(ethylamino)ethanol (0.89 g,10.0 mmol) yielded3-fluoro-N-{5-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}-benzamide(667 mg, 62% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 9.59 (s, 1H), 8.77 (d, 1H), 8.44 (s, 1H), 8.26 (dd,1H), 8.19 (d, 1H), 7.85 (m, 3H), 7.56 (m, 1H), 7.42 (m, 1H), 7.17 (s,1H), 4.35 (br s, 1H), 4.18 (t, 2H), 3.96 (s, 3H), 3.44 (q, 2H), 2.44 (m,6H), 1.91 (m, 2H), 0.97 (t, 3H):

MS (−ve ESI): 533.6 (M−H)⁻,

MS (+ve ESI): 535.6 (M+H)⁺.

EXAMPLE 8 Preparation of Compound 8 in Table1-2-[(3-{[4-({6-[(3,4-difluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isopropyl)amino]ethyldihydrogen phosphate

An analogous reaction to that described in example 7, but starting with3,4-difluoro-N-{5-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(652 mg, 1.15 mmol), yielded the title compound (as a dihydrochloridesalt, 398 mg, 45% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆+CD₃COOD): 8.76 (m, 2H), 8.29 (s, 1H), 8.22 (m, 2H), 8.10(m, 1H), 7.92 (m, 1H), 7.66 (s, 1H), 7.54 (dd, 1H), 7.37 (s, 1H), 4.41(t, 2H), 4.18 (m, 2H), 4.04 (s, 3H), 3.74 (m, 1H), 3.37 (m, 2H), 3.23(m, 2H), 2.26 (m, 2H), 1.28 (d, 6H):

MS (+ve ESI): 647.5 (M+H)⁺.

3,4-difluoro-N-{5-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 2a but startingwith 3,4-difluorobenzoyl chloride (19.4 g, 110 mmol) yieldedN-(5-nitropyridin-2-yl)-3,4-difluorobenzamide (24.9 g, 89% yield):

¹H-NMR (DMSO-d₆): 11.60 (br s, 1H), 9.20 (d, 1H), 8.63 (dd, 1H), 8.38(d, 1H), 8.11 (m, 1H), 7.92 (m, 1H), 7.59 (d, 1H):

MS (+ve ESI): 280.3 (M+H)⁺.

b) An analogous reaction to that described in example 2b but startingwith N-(5-nitropyridin-2-yl)-3,4-difluorobenzamide (24.7 g, 88.4 mmol)yielded N-(5-aminopyridin-2-yl)-3,4-difluorobenzamide (21 g, 95% yield)as an off-white powder:

¹H-NMR (DMSO-d₆): 10.44 (br s, 1H), 8.06 (m, 1H), 7.94 (m, 1H), 7.73 (m,1H), 7.00 (m, 1H), 5.18 (br s, 2H):

MS (+ve ESI): 250.3 (M+H)⁺.

c) An analogous reaction to that described in example 2c but startingwith N-(5-aminopyridin-2-yl)-3,4-difluorobenzamide (1.24 g, 5.0 mmol)yielded3,4-difluoro-N-(5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamidehydrochloride as a pale yellow solid (2.56 g, 96% yield):

¹H-NMR (DMSO-₆): 8.84 (s, 1H), 8.75 (d, 1H), 8.43 (s, 1H), 8.20 (m, 2H),8.10 (m, 1H), 7.93 (m, 1H), 7.59 (m, 1H), 7.41 (m, 1H), 4.28 (t, 2H),4.03 (s, 3H), 3.81 (t, 2H), 2.27 (m, 2H):

MS (−ve ESI): 498.5 (M−H)⁻,

MS (+ve ESI): 500.5 (M+H)⁺.

d) An analogous reaction to that described in example 2d but startingwith3,4-difluoro-N-(5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamidehydrochloride (0.40 g, 0.75 mmol) and 2-(isopropylamino)ethanol (0.39 g,3.75 mmol) yielded3,4-difluoro-N-{5-[(7-{3-[(2-hydroxyethyl)(isopropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(193 mg, 45% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 10.92 (s, 1H), 9.60 (s, 1H), 8.77 (d, 1H), 8.46 (s,1H), 8.26 (dd, 1H), 8.19 (d, 1H), 8.13 (m, 1H), 7.95 (m, 1H), 7.84 (s,1H), 7.57 (m, 1H), 7.17 (s, 1H), 4.21 (m, 3H), 3.96 (s, 3H), 3.36 (m,2H), 2.88 (m, 1H), 2.56 (m, 2H), 2.45 (m, 2H), 1.85 (m, 2H), 0.91 (d,6H) :

MS (−ve ESI): 565.4 (M−H)⁻,

MS (+ve ESI): 567.3 (M+H)⁺.

EXAMPLE 9 Preparation of Compound 9 in Table 11-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yldihydrogen phosphate

3-chloro-N-[5-({7-[3-(4-hydroxypiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}amino)pyridin-2-yl]benzamide(281 mg, 0.50 mmol) and dry 1 H-tetrazole (157 mg, 2.30 mmol) weredissolved in dry dimethylacetamide (10.6 ml). Di-tert-butyl-N,Ndiethylphosphoramidite (210 ul, 0.74 mmol) was added and the reactionstirred at ambient temperature for 2 hours. Further portions of 1H-tetrazole (157 mg, 2.3 mmol) anddi-tert-butyl-N,N-diethylphosphoramidite (210 μl, 0.74 mmol) were addedand the reaction mixture stirred for 18 hours. The reaction was cooledto −40° C. and 3-chloroperoxybenzoic acid (366 mg, 1.49 mmol) added. Thereaction was warmed to ambient temperature, concentrated and suspendedin a solution of sodium metabisulphite (10 ml of a 0.26 M solution).This was extracted with ethyl acetate and the organics washed withsodium bicarbonate (saturated solution), dried with magnesium sulphateand concentrated. Purification by flash chromatography on alumina,eluting with dichloromethane:methanol:saturated ammonia (97:2:1) yieldeddi-tert-butyl1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-ylphosphate as a yellow solid (210 mg, 56% yield):

¹H-NMR (DMSO-d₆): 10.91 (s, 1H), 9.59 (s, 1H), 8.77 (d, 1H), 8.45 (s,1H), 8.26 (dd, 1H), 8.18 (d, 1H), 8.09 (s, 1H), 7.98 (d, 1H), 7.82 (s,1H), 7.65 (d, 1H), 7.54 (t, 1H), 7.18 (s, 1H), 4.17 (m, 3H), 3.96 (s,3H), 3.36 (m, 2H), 2.62 (m, 2H), 2.44 (t, 2H), 2.21 (t, 2H), 1.87 (m,4H), 1.63, (m, 2H), 1.39 (s, 18H).

Hydrogen chloride (150 μl of a 4.0 N solution in 1,4-dioxane, 0.6 mmol)was added, dropwise to a solution of di-tert-butyl1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-ylphosphate (70 mg, 0.1 mmol) in 1,4-dioxane (3 ml). The resultingheterogeneous reaction mixture was stirred for a further hour anddiethyl ether was added (10 ml). The precipitate was filtered and washedwith diethyl ether (3×10 ml) then dried under high vacuum for 48 hoursto yield the title compound1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl dihydrogen phosphate(di-hydrochloride) as an off-white solid (34 mg, 53% yield):

¹H-NMR (DMSO-d₆): 11.98 (s, 1H), 11.11 (s, 1H), 8.87 (s, 1H), 8.79 (s,1H), 8.79 (s, 1H), 8.58 (s, 1H), 8.24 (s, 2H), 8.09 (s, 1H), 7.99 (d,1H), 7.68 (dd, 1H), 7.55 (t, 1H), 7.44 (s, 1H), 4.52 (m, 1H), 4.31 (t,2H), 4.05 (s, 3H), 3.49 (m, 2H), 3.24 (m, 2H), 3.08 (m, 2H), 2.35 (m,2H), 2.14 (m, 2H), 2.05 (t, 2H), 2.00 (m, 2H):

MS (+ve ESI): 643.2 (M+H)⁺.

3-chloro-N-[5-({7-[3-(4-hydroxypiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}amino)pyridin-2-yl]benzamide,used as the starting material was obtained as described in example 2dbut starting with 4-hydroxypiperidine (1.83 g, 18 mmol). The reactionyielded the desired compound as an off-white solid (860 mg, 85% yield):

¹H-NMR (DMSO-d₆): 10.48 (s, 1H), 9.35 (br s, 1H), 8.80 (s, 1H), 7.99 (d,1H), 7.84 (s, 1H), 7.61 (d, 1H), 7.53 (t, 1H), 7.21 (s, 1H), 4.22 (t,2H), 4.06 (s, 1H), 3.99 (s, 3H), 3.49 (m, 1H), 2.72 (m, 2H), 2.48 (m,2H), 2.11 (d, 2H), 1.95 (m, 2H), 1.72 (m, 2H), 1.43 (m, 2H):

MS (+ve ESI): 563 (M+H)⁺.

EXAMPLE 10 Preparation of Compound 10 in Table1-4-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}butyldihydrogen phosphate

An analogous reaction to that described in example 9, but starting with3-chloro-N-(5-{[7-(4-hydroxybutoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamide(493 mg, 1.0 mmol) yielded the title compound as a pale yellow solid(250 mg, 88% yield):

¹H-NMR (DMSO-d₆): 11.81 (s, 1H), 11.08 (s, 1H), 8.85 (s, 1H), 8.76 (d,1H), 8.46 (s, 1H), 8.23 (m, 2H), 8.09 (s, 1H), 7.98 (d, 1H), 7.67 (d,1H), 7.55 (t, 1H), 7.41 (s, 1H), 4.22 (t, 2H), 4.04 (s, 3H), 3.91 (q,2H), 1.91 (m, 2H), 1.77 (m, 2H):

³¹P-NMR (DMSO-d₆): 0.00 (t, 1P):

MS (+ve ESI): 574 (M+H)⁺.

3-chloro-N-(5-{[7-(4-hydroxybutoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamideused as the starting material was obtained as follows:

a) An analogous reaction to that described in example 2c, but startingwith 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (615 mg, 1.12 mmol-seeWO 9722596) and N-(5-aminopyridin-2-yl)-3-chlorobenzamide ( 362 mg, 1.46mmol) affordedN-(5-{[7-(benzyloxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)-3-chlorobenzamide(625 mg, 78% yield):

¹H-NMR (DMSO-d₆): 11.23 (s, 1H), 10.65 (br s, 1H), 8.82 (s, 1H), 8.73(s, 1H), 8.40 (s, 1H), 8.25 (m, 2H), 8.10 (s, 1H), 8.02 (d, 1H), 7.65(d, 1H), 7.53 (m, 4H), 7.38 (m, 3H), 5.36 (s, 2H), 4.08 (s, 3H).

b)N-(5-{[7-(benzyloxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)-3-chlorobenzamide(615 mg, 1.12 mmol) was dissolved in trifluoroacetic acid (6 ml) andheated to 90° C. for 2 hours. The excess trifluoroacetic acid wasevaporated and water was added cautiously to the slurry. This was addedto a solution of ammonia (10 ml) and stirred rapidly. The resultingprecipitate was isolated, washed with water and dried under high vacumm.The solid was triturated with acetone to afford3-chloro-N-{5-[(7-hydroxy-6-methoxyquinazolin-4yl)amino]pyridin-2-yl}benzamide(435 mg, 92% yield):

¹H-NMR (DMSO-d₆): 10.90 (s, 1H), 10.32 (s, 1H), 9.53 (s, 1H), 8.77 (d,1H), 8.39 (s, 1H), 8.25 (m, 1H), 8.18 (d, 1H), 8.09 (s, 1H), 7.98 (d,1H), 7.81 (s, 1H), 7.65 (d, 1H), 7.53 (t, 1H), 7.06 (s, 1H), 3.97 (s,3H):

MS (+ve ESI): 422 (M+H)⁺.

c)3-chloro-N-{5-[(7-hydroxy-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(431 mg, 1.01 mmol), 4-bromobutyloxyacetate (294 mg, 1.5 mmol) andpotassium carbonate (414 mg, 3.00 mmol) were dissolved indimethylacetamide (15 ml) and stirred at ambient temperature for 18hours. The reaction mixture was concentrated and water (10 ml) added.The resultant precipitate was removed by filtration, washed with waterand dried under high vacuum. The solid was recrystallised fromacetonitrile to afford4-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}butylacetate (337 mg, 63% yield):

¹H-NMR (DMSO-d₆): 8.76 (s, 1H), 8.45 (s, 1H), 8.26 (m, 1H), 8.20 (d,1H), 8.09 (s, 1H), 7.99 (d, 1H), 7.83 (s, 1H), 7.66 (d, 1H), 7.54 (t,1H), 7.19 (s, 1H), 4.18 (t, 2H), 4.08 (t, 2H), 3.95 (s, 3H), 2.00 (s,3H), 1.84 (m, 2H), 1.75 (m, 2H):

MS (+ve ESI): 536 (M+H)⁺.

d)4-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}butylacetate (100 mg, 0.18 mmol) was dissolved in methanol (2.5 ml) and water(2.5 ml). Sodium hydroxide (15 mg, 0.36 mmol) was added and the reactionheated to 90° C. for 1 hour. The reaction was cooled and the precipitatewas isolated by filtration, washed with water and dried under highvacuum to yield3-chloro-N-(5-{[7-(4-hydroxybutoxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamide(64 mg, 72% yield):

¹H-NMR (DMSO-d₆): 10.91 (s, 1H), 9.59 (s, 1H), 8.77 (d, 1H), 8.47 (s,1H), 8.26 (m, 1H), 8.19 (d, 1H), 8.09 (s, 1H), 7.99 (d, 1H), 7.83 (s,1H), 7.66 (d, 1H), 7.54 (t, 1H), 7.18 (s, 1H), 4.45 (t, 1H), 4.14 (t,2H), 3.97 (s, 3H), 3.47 (q, 2H), 1.84 (m, 2H), 1.61 (m, 2H):

MS (+ve ESI): 494 (M+H)⁺.

EXAMPLE 11 Preparation of Compound 11 in Table1-2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyguinazolin-7-yl]oxy}propyl)(methyl)amino]ethyldihydrogen phosphate

Di-tert-butyl-N,N-diethylphosphoramidite (730 μl, 2.60 mmol) was addedto a mixture of3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)(methyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(1.00 g, 1.86 mmol) and dry 1 H-tetrazole (400 mg, 5.59 mmol) indimethylacetamide (25 ml). The reaction was stirred under an inertatmosphere at ambient temperature for 18 hours. Dichloromethane (150 ml)and aqueous sodium hydrogen carbonate solution (50 ml) were added andthe reaction mixture stirred briefly. The aqueous layer was extractedwith dichloromethane and the combined organics dried (sodium sulphate)and concentrated to give a yellow oil which was taken up intetrahydrofuran (15 ml). The mixture was cooled to 0° C. and 30% aqueoushydrogen peroxide (0.50 ml, 3.72 mrnol) was added slowly and thereaction was stirred at 0° C. for 1 hour. A further equivalent of 30%aqueous hydrogen peroxide was added and the reaction allowed to warm toambient temperature. The reaction was cooled to 0° C. and a solution ofsodium metabisulphite (30 ml, 0.52 M solution) was added. This mixturewas warmed to ambient temperature and extracted with ethyl acetate(4×100 ml). The combined organics were dried (sodium sulphite) andconcentrated to afford the crude phosphate ester as a yellow oil:

MS (+ve ESI) : 729 (M+H)⁺.

This was taken up in dioxane (70 ml) and treated dropwise with a 4.0 Nsolution of hydrogen chloride in dioxane (5 ml, 20 mmol). The whiteslurry was stirred at ambient temperature for 18 hours and diethyl etherwas added (200 ml). The precipitate was filtered and washed with diethylether (3×30 ml) then dried under high vacuum to yield the title compound2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(methyl)amino]ethyldihydrogen phosphate (di-hydrochloride) as an off-white solid (1.2 g,93% yield):

¹H-NMR (DMSO-d₆): 11.95 (m, 1H), 11.11 (s, 1H), 8.88 (s, 1H), 8.81 (s,1H), 8.59 (m, 1H), 8.25 (m, 2H), 8.11 (m, 1H), 8.03 (d, 1H), 7.68 (m,1H), 7.56 (t, 1H), 7.50 (m, 1H), 4.26 (m, 4H), 4.06 (s, 3H), 3.44 (m,2H), 3.35 (m, 2H), 2.88 (s, 3H), 2.34 (m, 2H):

MS (+ve ESI) : 617 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)(methyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamideused as the starting material was obtained as described in example 2dbut starting with 2-(methylamino)ethanol (210 mg, 2.80 mmol). Thereaction yielded the desired compound as an off-white solid (51 mg, 34%yield):

¹H-NMR (DMSO-d₆): 10.50 (s, 1H), 9.41 (s, 1H), 8.81 (s, 1H), 8.46 (s,1H), 8,27 (dd, 1H), 8.15 (d, 1H), 8.08 (s, 1H), 7.99 (d, 1H), 7.88 (s,1H), 7.62 (d, 1H), 7.53 (t, 1H), 7.22 (s, 1H), 4.24 (t, 2H), 4.02 (s,3H), 3.57 (t, 2H), 2.75 (t, 2H), 2.65 (t, 2H), 2.38 (s, 3H), 2.02 (m,2H),

MS (+ve ESI) : 537 (M+H)⁺.

EXAMPLE 12 Preparation of Compound 12 in Table1-[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-2-yl]methyldihydrogen phosphate

Di-tert-butyl-N,N-diethylphosphoramidite (136 μl, 0.49 mmol) was addedto a mixture of3-chloro-N-{5-[(7-{3-[2-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(202 mg, 0.35 mmol) and dry 1 H-tetrazole (61 mg, 0.87 mmol) indimethylacetamide (0.5 ml). The reaction was stirred under an inertatmosphere at ambient temperature for 18 hours before addition ofanother equivalent of each reagent and further stirring for 6 hours.Dichloromethane (10 ml) and methanol (0.5 ml) were added and the mixturewashed with aqueous potassium carbonate solution (20%, 10 ml). Theorganics were dried (magnesium sulphate) and concentrated to give ayellow oil which was taken up in tetrahydrofuran (2 ml). The mixture wascooled to 0° C. and 30% aqueous hydrogen peroxide (72 μl, 0.7 mmol) wasadded slowly and the reaction was stirred at 0° C. for 1 hour. A furtherequivalent of 30% aqueous hydrogen peroxide was added and the reactionallowed to warm to ambient temperature. The reaction was cooled to 0° C.and a solution of sodium metabisulphite (0.5 ml, 0.52 M solution) wasadded. This mixture was warmed to ambient temperature and extracted withdichloromethane: methanol (10:1). The combined organics were dried(magnesium sulphate) and concentrated to afford the crude phosphateester as a yellow oil. This was taken up in dioxane (11 ml) and treateddropwise with a 4.0 N solution of hydrogen chloride in dioxane (0.55 ml,2.20 mmol). The white slurry was stirred at ambient temperature for 18hours and diethyl ether was added (200 ml). The precipitate was filteredand washed with acetonitrile then purified according to the methoddescribed in example 2 to yield the title compound1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-2-yl]methyldihydrogen phosphate (di-hydrochloride) as an off-white solid (140 mg,64% yield):

¹H-NMR (DMSO-d₆+CD₃COOD): 8.75 (s, 1H), 8.60 (br s, 1H), 8.22 (m, 2H),8.06 (s, 1H), 7.98 (m, 2H), 7.61 (m, 1H), 7.50 (m, 1H), 7.42 (s, 1H),4.29 (t, 2H), 4.11 (m, 1H), 3.99 (s, 3H), 3.85 (m, 1H), 3.23 (m, 1H),3.09 (m, 1H), 2.52 (m, 2H), 2.25 (m, 2H), 1.73 (m, 5H), 1.50 (m, 2H):

MS (+ve ESI): 657 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[2-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamideused as the starting material was obtained as described in example 2dbut starting with 2-(hydroxymethyl)piperidine (323 mg, 2.8 mmol). Thereaction yielded the desired compound as an off-white solid (63 mg, 39%yield):

¹H-NMR (DMSO-d₆): 10.50 (s, 1H), 9.37 (s, 1H), 8.82 (s, 1H), 8.49 (s,1H), 8.27 (dd, 1H), 8.16 (d, 1H), 8.10 (s, 1H), 8.01 (d, 1H), 7.86 (s,1H), 7.63 (d, 1H), 7.56 (t, 1H), 7.23 (s, 1H), 4.24 (t, 2H), 4.02 (s,3H), 3.62 (m, 1H), 3.44 (m, 1H), 2.89 (m, 2H), 2.60 (m, 1H), 2.39 (m,1H), 2.27 (m, 1H), 1.97 (t, 2H), 1.68-1.13 (m, 6H):

MS (+ve ESI): 577 (M+H)⁺.

EXAMPLE 13 Preparation of Compound 13 in Table1-2-[(5-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}pentyl)(ethyl)amino]ethyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-(5-{[7-({5-[ethyl(2-hydroxyethyl)amino]pentyl}oxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamide(350 mg, 0.60 mmol), yielded the title compound (as the di-hydrochloridesalt, 340 mg, 77% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 11.88 (br s, 1H), 11.05 (br s, 1H), 8.81 (m, 2H), 8.53(s, 1H), 8.25 (m, 2H), 8.09 (s, 1H), 7.98 (d, 1H), 7.67 (m, 1H), 7.55(t, 1H), 7.44 (s, 1H), 7.51 (m, 3H), 4.26 (m, 4H), 4.06 (s, 3H), 3.38(m, 2H), 3.15 (m, 4H), 1.82 (m, 4H), 1.49 (m, 2H), 1.23 (m, 3H):

MS (+ve ESI): 659 (M+H)⁺.

3-chloro-N-(5-{[7-({5-[ethyl(2-hydroxyethyl)amino]pentyl}oxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 10c but startingwith bromo-5-chloropentane (280 mg, 1.50 mmol) yielded3-chloro-N-[5-({7-[(5-chloropentyl)oxy]-6-methoxyquinazolin-4-yl}amino)pyridin-2-yl]benzamide(162 mg, 20% yield):

¹H-NMR (DMSO-d₆): 10.90 (s, 1H), 9.61 (s, 1H), 8.77 (s, 1H), 8.48 (s,1H), 8.23 (m, 2H), 8.09 (s, 1H), 7.83 (s, 1H), 7.66 (d, 1H), 7.55 (t,1H), 7.18 (s, 1H), 4.15 (t, 2H), 3.96 (s, 3H), 3.67 (t, 2H), 1.84 (m,4H), 1.57 (m, 2H).

b) An analogous reaction to that described in example 2d but startingwith 2-(ethylamino)ethanol (93 mg, 0.95 mmol) and3-chloro-N-[5-({7-[(5-chloropentyl)oxy]-6-methoxyquinazolin-4-yl}amino)pyridin-2-yl]benzamide(100 mg, 0.19 mmol) yielded3-chloro-N-(5-{[7-({5-[ethyl(2-hydroxyethyl)amino]pentyl}oxy)-6-methoxyquinazolin-4-yl]amino}pyridin-2-yl)benzamide(50 mg, 45% yield):

¹H-NMR (DMSO-d₆) :11.22 (m, 1H), 11.05 (br s, 1H), 8.82 (s, 1H), 8.70(d, 1H), 8.27 (m, 1H), 8.14 (m, 2H), 8.09 (m, 1H), 7.98 (m, 1H), 7.66(m, 1H), 7.54 (m, 1H), 7.40 (s, 1H), 4.20 (t, 2H), 3.99 (s, 3H), 3.71(t, 2H), 3.17 (m, 6H), 1.84 (m, 2H), 1.72 (m, 2H), 1.45 (m, 2H), 1.20(t, 3H):

MS (−ve ESI): 577 (M−H)⁻,

MS (+ve ESI): 579 (M+H)⁺.

EXAMPLE 14 Preparation of Compound 14 in Table1-4-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]butyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-{5-[(7-{3-[ethyl(4-hydroxybutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(1.02 g, 1.76 mmol) yielded the title compound (as the dihydrochloridesalt, 600 mg, 47% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 11.90 (br s, 1H), 11.61 (br s, 1H), 8.81 (m, 2H), 8.55(s, 1H), 8.25 (m, 2H), 8.09 (s, 1H), 7.98 (d, 1H), 7.67 (m, 1H), 7.55(t, 1H), 7.44 (s, 1H), 4.30 (m, 2H), 4.03 (s, 3H), 3.19 (m, 6H), 2.88(m, 2H), 2.30 (m, 2H), 1.78 (m, 2H), 1.66 (m, 2H), 1.25 (m, 3H):

MS (+ve ESI): 659 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[ethyl(4hydroxybutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as described in example 2d,but starting with 4-(ethylamino)butanol (226 ml, 1.93 mmol). Thereaction yielded the desired compound as the di-trifluoroacetic acidsalt ( 113 mg, 51% yield):

¹H-NMR (DMSO-d₆): 11.04 (s, 1H), 10.99 (br s, 1H), 8.81 (s, 1H), 8.70(m, 1H), 8.28 (m, 1H), 8.16 (m, 1H), 8.08 (m, 2H), 7.98 (m, 1H), 7.67(m, 1H), 7.55 (t, 1H), 7.38 (s, 1H), 4.30 (t, 2H), 3.99 (s, 3H), 3.42(t, 2H), 3.20 (m, 6H), 2.22 (m, 2H), 1.70 (m, 2H), 1.48 (m, 2H), 1.22(t, 3H):

MS (−ve ESI): 577 (M−H)⁻,

MS (+ve ESI): 579 (M+H)⁺.

EXAMPLE 15 Preparation of Compound 15 in Table1-2-[(3-{[4-({6-[(3-fluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(methyl)amino]ethyldihydrogen phosphate

An analogous reaction to that described in example 7, but starting with3-fluoro-N-{5-[(7-{3-[(2-hydroxyethyl)(methyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(1.10 g, 2.11 mmol) yielded the title compound (as the formate salt, 180mg, 13% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 12.15 (br s, 1H), 10.99 (br s, 1H), 8.81 (m, 2H), 8.64(s, 1H), 8.25 (m, 1H), 7.88 (m, 2H), 7.51 (m, 3H), 4.26 (m, 4H), 4.06(s, 3H), 3.43 (m, 2H), 3.34 (m, 2H), 2.86 (s, 3H), 2.34 (m, 2H):

MS (+ve ESI): 601 (M+H)⁺.

3-fluoro-N-{5-[(7-{3-[(2-hydroxyethyl)(methyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 7d, but startingwith 2-(methylamino)ethanol (780 μl, 9.67 mmol) yielded3-fluoro-N-{5-[(7-{3-[(2-hydroxyethyl)methyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(1.2 g, 72% yield):

¹H-NMR (DMSO-d₆): 10.85 (m, 1H), 9.61 (s, 1H), 8.78 (m, 1H), 8.45 (s,1H), 8.28 (m, 1H), 8.19 (m, 1H), 7.87 (m, 3H), 7.55 (m, 1H), 7.43 (m,1H), 7.18 (s, 1H), 4.43 (m, 1H), 4.16 (t, 2H), 3.98 (s, 3H), 3.44 (m,2H), 2.50 (m, 2H), 2.41 (t, 2H), 2.20 (s, 3H), 1.89 (m, 2H),

MS (−ve ESI): 519 (M−H)⁻,

MS (+ve ESI): 521 (M+H)⁺.

EXAMPLE 16 Preparation of Compound 16 in Table1-2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isobutyl)amino]ethyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(60 mg, 0.10 mmol), initially yielded di-tert-butyl2-[(3-{[4-({6-[(3-chlorobenzoyl)amino[pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isobutyl)amino]ethylphosphate (34 mg, 42% yield):

¹H-NMR (DMSO-d₆): 10.92 (s, 1H), 9.60 (s, 1H), 8.80 (d, 1H), 8.45 (s,1H), 8.25 (dd, 1H), 8.20 (d, 1H), 8.05-8.02 (m, 1H), 8.0 (d, 1H), 7.80(s, 1H), 7.65-7.60 (m, 1H), 7.55-7.50 (m, 1H), 7.20 (s, 1H), 4.20 (t,2H), 4.0 (s, 3H), 3.85-3.80 (m, 2H), 2.65-2.60 (m, 4H), 2.20 (d, 2H),1.95-1.80 (m, 2H), 1.40 (s, 18H), 0.85-0.80 (m, 7H):

MS (−ve ESI): 769 (M−H)⁻,

MS (+ve ESI): 771 (M+H)⁺.

di-tert-butyl2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isobutyl)amino]ethylphosphate was subjected to deprotection with hydrochloric acid(according to the method described in example 12 to yield the titlecompound (as the di-hydrochloride salt, 30 mg, 93% yield) as a paleyellow solid:

¹H-NMR (DMSO-d₆): 12.00 (s, 1H), 11.00 (s, 1H), 8.90 (s, 1H), 8.80 (s,1H), 8.60 (s, 1H), 8.30-8.40 (m, 2H), 8.10 (s, 1H), 8.01 (d, 1H), 7.65(d, 1H), 7.47 (m, 1H), 7.40 (s, 1H), 4.30-4.40 (m, 2H), 4.00 (s, 3H),3.50-3.60 (m, 2H), 3.30-3.40 (m, 2H), 3.10 (d, 2H), 2.30-2.40 (m, 2H),2.10-2.20 (m, 1H), 1.10 (s, 3H), 1.00 (s, 3H):

MS (−ve ESI): 657 (M−H)⁻,

MS (+ve ESI): 659 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)(isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) A cooled (−60° C.) solution of ethylene oxide (5.28 g, 120 mmol) inmethanol (14 ml), was added slowly to a solution of isobutylamine (30.7g, 420 mmol) in methanol (100 ml) at −65° C. under argon. The mixturewas allowed to warm to ambient temperature over 14 hours, concentratedin vacuo and the residual oil was purified by distillation (b.p. 130° C./0.5 mmHg) to yield 2-(isobutylamino)ethanol (11 g, 78% yield):

¹H-NMR (DMSO d₆): 4.40 (m, 1H), 3.42 (m, 2H), 2.50 (m, 2H), 2.30 (d,2H), 1.63 (m, 1H), 0.85 (d, 6H).

b) An analogous reaction to that described in example 2d, but startingwith 2-(isobutylamino)ethanol (263 mg, 2.25 mmol) yielded3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)isobutyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(80 mg, 18% yield):

¹H-NMR (DMSO-d₆): 10.91 (s, 1H), 9.60 (s, 1H), 8.80 (d, 1H), 8.45 (s,1H), 8.25 (dd, 1H), 8.20 (d, 1H), 8.04 (m, 1H), 8.00 (d, 1H), 7.80 (s,1H), 7.62 (m, 1H), 7.53 (m, 1H), 7.20 (s, 1H), 4.25 (br s, 1H), 4.20 (t,2H), 4.00 (s, 3H), 3.40 (t, 2H), 2.60 (t, 2H), 2.20 (d, 2H), 1.80-1.95(m, 2H), 1.60-1.70 (m, 1H), 0.80 (s, 3H), 0.78 (s, 3H):

MS (−ve ESI): 577, 579 (M−H)⁻,

MS (+ve ESI): 579, 581 (M+H)⁺.

EXAMPLE 17 Preparation of Compound 17 in Table1-2-[3-{[4-({6-f(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclopropyl)amino]ethyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-{5-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(130 mg, 0.23 mmol), initially yielded di-tert-butyl2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclopropyl)amino]ethylphosphate (170 mg, quantitative yield):

¹H-NMR (DMSO-d₆): 11.00 (s, 1H), 10.60 (s, 1H), 8.80 (d, 1H), 8.45 (s,1H), 8.25 (dd, 1H), 8.10 (d, 1H), 8.00 (d, 1H), 7.80 (s, 1H), 7.62 (m,1H), 7.50-7.60 (m, 1H), 7.20 (s, 1H), 4.20 (t, 2H), 4.00 (s, 3H), 3.88(m, 2H), 2.83 (m, 4H), 1.90-2.00 (m, 2H), 1.82 (m, 1H), 1.40 (s, 18H),0.42 (m, 2H), 0.27 (m, 2H):

MS (−ve ESI): 753 (M−H)⁻,

MS (+ve ESI): 755 (M+H)⁺.

di-tert-butyl2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclopropyl)amino]ethylphosphate was subjected to deprotection with hydrochloric acid(according to the method described in example 12 to yield the titlecompound (as the di-hydrochloride salt, 30 mg, 93% yield) as a paleyellow solid:

¹H-NMR (DMSO-d₆): 12.00 (s, 1H), 11.20 (s, 1H), 9.00 (s, 1H), 8.80 (s,1H), 8.60 (s, 1H), 8.40-8.50 (m, 2H), 8.20 (s, 1H), 8.0 (d, 1H), 7.68(m, 1H), 7.50-7.60 (m, 1H), 7.45 (s, 1H), 4.40-4.50 (m, 4H), 4.20 (s,3H), 3.60-3.70 (m, 2H), 3.40-3.50 (m, 2H), 3.0003.10 (m, 1H), 2.50-2.60(m, 2H), 1.30-1.40 (m, 2H), 1.00-1.10 (m, 2H):

MS (+ve ESI): 643, 645 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) A solution of triethylamine (15.6 g, 154 mmol) and cyclopropylamine(4.85 ml, 70 mmol) in diethyl ether (50 ml) was added dropwise to astirred solution of ethyloxalyl chloride (8.59 ml, 77 mmol) in diethylether (75 ml) at 0° C. The reaction was allowed to warm to ambienttemperature over 1 hour, was filtered and then concentrated in vacuo toyield ethyl (cyclopropylamino)(oxo)acetate as a brown oil which was usedwithout further purification (12.5 g, quantitative yield):

¹H-NMR (DMSO-d₆): 8.85 (s, 1H), 4.20 (q, 2H), 2.70-2.80 (m, 1H), 1.25(t, 3H), 0.60-0.70 (m, 2H), 0.56 (m, 2H):

MS (+ve ESI): 158 (M+H)⁺.

b) Chloromethylsilane (68 ml, 539 mmol) was added to a stirred solutionof lithium borohydride in tetrahydrofuran (135 ml of a 2.0 N solution,270 mmol) at ambient temperature. The reaction was cooled to 0° C. and asolution of ethyl (cyclopropylamino)(oxo)acetate (12.5 g from previousexperiment, assumed 70 mmol) in tetrahydrofuran (100 ml) was added over5 minutes before the reaction as allowed to warm to ambient temperatureover 2 hours. Methanol (10 ml) was added, the reaction was allowed tostand overnight and the volatiles were removed in vacuo. The residue wasstirred with 1.0 N aqueous sodium hydroxide solution and extracted withdichloromethane (3×25 ml). Purification by flash chromatography onsilica gel, eluting with 5-20% methanol in dichloromethane, yielded2-(cyclopropylamino)ethanol (1.45 g, 20% yield) as a colourless oil:

¹ H-NMR (DMSO-d₆): 3.25 (t, 2H), 2.45 (t, 2H), 1.85-2.00 (m, 1H),0.15-0.55 (m, 2H), 0.02 (m, 2H):

MS (+ve ESI): 102 (M+H)⁺.

c) An analogous reaction to that described in example 2d, but startingwith 2-(cyclopropylamino)ethanol (783 mg, 1.47 mmol) yielded3-chloro-N-{5-[(7-{3-[cyclopropyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(80 mg, 18% yield):

¹H-NMR (DMSO-d₆): 9.40 (br s, 1H), 8.50 (d, 1H), 8.20 (s, 1H), 8.00 (dd,1H), 7.95 (d, 1H), 7.80 (s, 1H), 7.70 (d, 1H), 7.55 (s, 1H), 7.40 (dd,1H), 7.25 (m, 1H), 6.90 (s, 1H), 4.00 (t, 1H), 3.90 (t, 2H), 3.70 (s,3H), 3.22 (m, 2H), 2.50 (t, 2H), 2.40 (t, 2H), 1.65-1.80 (m, 2H),1.50-1.60 (m, 2H), 0.10-0.20 (m, 2H), 0.02 (m, 2H):

MS (−ve ESI) : 561, 563 (M−H)⁻,

MS (+ve ESI): 563, 565 (M+H)⁺.

EXAMPLE 18 Preparation of Compound 18 in Table1-[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl]methyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-{5-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(1.02 g, 1.77 mmol), initially yielded di-tert-butyl[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl]methylphosphate (881 mg, 64% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 11.0 (br s, 1H), 9.60 (s, 1H), 8.85 (s, 1H), 8.50 (s,1H), 8.30 (dd, 1H), 8.20 (d, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.90 (s,1H), 7.70 (d, 1H), 7.62 (m, 1H), 7.20 (s, 1H), 4.20 (t, 2H), 4.00 (s,3H), 3.70 (t, 2H), 2.90-3.00 (m, 2H), 2.40-2.50 (m, 2H), 1.90-2.10 (m,4H), 1.60-1.70 (m, 3H), 1.40 (s, 18H), 1.32 (m, 2H):

MS (+ve ESI): 767, 769 (M+H)⁺.

di-tert-butyl[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl]methylphosphate (771 mg, 1.00 mmol) was subjected to deprotection withhydrochloric acid (according to the method described in example 12 toyield the title compound (as the di-hydrochloride salt, 705 mg, 96%yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 12.00 (s, 1H), 11.10 (s, 1H), 10.50 (s, 1H), 8.90 (s,1H), 8.85 (s, 1H), 8.70 (s, 1H), 8.30-8.40 (m, 2H), 8.15 (s, 1H), 8.05(d, 1H), 7.70 (d, 1H), 7.57 (m, 1H), 7.50 (s, 1H), 4.30-4.40 (m, 2H),4.15 (s, 3H), 3.70 (t, 2H), 3.62 (m, 2H), 3.30-3.40 (m, 2H), 2.90-3.10(m, 2H), 2.42 (m, 2H), 1.90-2.00 (m, 3H), 1.60-1.80 (m, 2H):

MS (−ve ESI): 655 (M−H)⁻,

MS (+ve ESI): 657 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 2d, but startingwith 4-piperidinemethanol (647 mg, 5.63 mmol) yielded3-chloro-N-{5-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin4-yl)amino]pyridin-2-yl}benzamide(1.02 g, 94% yield):

¹H-NMR (DMSO-d₆): 10.91 (br s, 1H), 9.65 (s, 1H), 8.80 (d, 1H), 8.40 (s,1H), 8.30 (dd, 1H), 8.20 (d, 1H), 8.05 (s, 1H), 8.00 (d, 1H), 7.85 (s,1H), 7.60 (d, 1H), 7.50-7.60 (m, 1H), 7.20 (s, 1H), 4.20-4.40 (m, 1H),4.20 (t, 2H), 4.00 (s, 3H), 3.20-3.40 (m, 6H), 2.00-2.20 (m, 2H),1.65-1.80 (m, 2H), 1.20-1.60 (m, 3H):

MS (+ve ESI): 577, 579 (M+H)⁺.

EXAMPLE 19 Preparation of Compound 19 in Table1-2-[4-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperazin-1-yl]ethyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-{5-[(7-{3-[4-(hydroxymethyl)piperidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(842 mg, 1.42 mmol), initially yielded di-tert-butyl2-[4-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperazin-1-yl]ethylphosphate (609 mg, 55% yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 10.80 (s, 1H), 9.70 (s, 1H), 8.80 (s, 1H), 8.50 (s,1H), 8.40 (dd, 1H), 8.20 (d, 1H), 8.10 (s, 1H), 8.00 (d, 1H), 7.90 (s,1H), 7.70 (d, 1H), 7.50-7.60 (m, 1H), 7.20 (s, 1H), 4.20 (t, 2H), 4.00(s, 3H), 3.90-4.00 (m, 2H), 2.60-2.70 (m, 2H), 2.30-2.50 (m, 10H),2.00-2.10 (m, 2H), 1.40 (s, 18H):

MS (−ve ESI): 782 (M−H)⁻,

MS (+ve ESI): 784 (M+H)⁺.

di-tert-butyl2-[4-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperazin-1-yl]ethylphosphate (609 mg, 0.78 mmol) was subjected to deprotection withhydrochloric acid (according to the method described in example 12 toyield the title compound (as the di-hydrochloride salt, 587 mg, 96%yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆): 12.00 (s, 1H), 11.20 (s, 1 H), 8.90 (s, 1H), 8.80 (s,1H), 8.60 (s, 1H), 8.30-8.40 (m, 2H), 8.20 (s, 1H), 8.00 (d, 1H), 7.70(d, 1H), 7.50-7.60 (m, 1H), 7.40 (s, 1H), 4.20-4.30 (m, 2H), 4.10 (s,3H), 3.50-3.90 (m, 6H), 3.30-3.40 (m, 2H), 3.23 (m, 2H), 3.10-3.20 (m,2H), 2.30-2.40 (m, 2H):

MS (−ve ESI): 670 (M−H)⁻,

MS (+ve ESI): 672 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 2d, but startingwith 4-hydroxyethyl piperazine (585 mg, 4.50 mmol) yielded3-chloro-N-{5-[(7-{3-[4-(2-hydrohydroxyethyl)piperazin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(842 mg, 94% yield):

¹H-NMR (DMSO-d₆): 10.90 (s, 1H), 9.60 (s, 1H), 8.80 (d, 1H), 8.45 (s,1H), 8.25 (dd, 1H), 8.20 (d, 1H), 8.04 (m, 1H), 7.98 (d, 1H), 7.85 (s,1H), 7.65 (d, 1H), 7.50-7.60 (m, 1H), 7.20 (s, 1H), 4.20 (t, 2H), 4.00(s, 3H), 3.50-3.60 (m, 2H), 3.20 (s, 1H), 2.60-3.00 (m, 10H), 1.90-2.10(m, 2H):

MS (+ve ESI) : 590, 592 (M+H)⁺.

EXAMPLE 20 Preparation of Compound 20 in Table1-[(2S)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)pyrrolidin-2-yl]methyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-{5-[(7-{3-[(2S)-2-hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(670 mg, 1.19 mmol), initially yielded di-tert-butyl[(2S)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)pyrrolidin-2-yl]methylphosphate (512 mg, 57% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 10.90 (s, 1H), 9.60 (s, 1H), 8.79 (s, 1H), 8.45 (s,1H), 8.25 (d, 1H), 8.20 (d, 1H), 8.09 (s, 1H), 8.00 (d, 1H), 7.85 (s,1H), 7.67 (d, 1H), 7.46 (t, 1H), 7.19 (s, 1H), 4.21 (m, 2H), 3.98 (s,3H), 3.79 (m, 1H), 3.58 (m, 1H), 3.09 (m, 1H), 2.95 (m, 1H), 2.69 (m,1H), 2.22 (m, 1H), 1.95 (m, 2H), 1.87 (m, 1H), 1.71 (m, 2H), 1.61 (m,1H), 1.38 (s, 9H):

MS (+ve ESI): 755 (M+H)⁺.

di-tert-butyl[(2S)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)pyrrolidin-2-yl]methylphosphate (512 mg, 0.68 mmol) was subjected to deprotection withhydrochloric acid (according to the method described in example 12 toyield the title compound (as the di-hydrochloride salt, 393 mg, 90%yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 11.95 (s, 1H), 11.07 (s, 1H), 8.85 (s, 1H), 8.79 (s,1H), 8.58 (s, 1H), 8.24 (m, 2H), 8.09 (s, 1H), 8.00 (d, 1H), 7.67 (d,1H), 7.55 (t, 1H), 7.47 (s, 1H), 4.31 (m, 2H), 4.23 (m, 2H), 4.03 (s,3H), 3.79 (m, 1H), 3.69 (m, 1H), 3.59 (m, 1H), 3.30 (m, 1H), 3.20 (m,1H),2.35 (m, 2H), 2.19 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.81 (m,1H):

MS (+ve ESI) : 643 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 2d, but startingwith L-prolinol (606 mg, 6.00 mmol) yielded3-chloro-N-{5-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(694 mg, 62% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 10.10 (br s, 1H), 8.77 (s, 1H), 8.45 (s, 1H), 8.24 (d,1H), 8.18 (d, 1H), 8.08 (s, 1H), 8.00 (d, 1H), 7.82 (s, 1H), 7.65 (d,1H), 7.55 (t, 1H), 7.18 (s, 1H), 4.27 (m, 1H), 4.18 (t, 2H), 3.96 (s,3H), 3.38 (dd, 1H), 3.18 (m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 2.41 (m,2H), 2.13 (dd, 1H), 1.93 (m, 2H), 1.79 (m, 1H), 1.62 (m, 2H), 1.51 (m,1H):

MS (+ve ESI): 563 (M+H)⁺.

EXAMPLE 21 Preparation of Compound 21 in Table1-2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclobutyl)amino]ethyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-{5-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(545 mg, 0.95 mmol), initially yielded di-tert-butyl2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclobutyl)amino]ethylphosphate (210 mg, 29% yield) as a yellow solid:

¹H-NMR (DMSO-d₆): 11.00 (s, 1H), 9.70 (s, 1H), 8.80 (s, 1H), 8.50 (s,1H), 8.40 (d, 1H), 8.20 (d, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.90 (s,1H), 7.70 (d, 1H), 7.50-7.60 (m, 1H), 7.20 (s, 1H), 4.20 (t, 2H), 4.00(s, 3H), 3.80-3.90 (m, 2H), 2.60-2.70 (m, 4H), 1.90-2.00 (m, 4H),1.70-1.80 (m, 2H), 1.50-1.60 (m, 2H), 1.40 (s, 18H):

MS (−ve ESI): 767, 769 (M−H)⁻,

MS (+ve ESI): 769, 771 (M+H)⁺.

di-tert-butyl2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclobutyl)amino]ethylphosphate (609 mg, 0.78 mmol) was subjected to deprotection withhydrochloric acid (according to the method described in example 12 toyield the title compound (as the di-hydrochloride salt, 180 mg, 90%yield) as a pale yellow solid:

¹H-NMR (DMSO-d₆):12.00 (s, 1H), 11.20 (s, 1H), 8.90 (s, 1H), 8.85 (s,1H), 8.70 (s, 1H), 8.30-8.40 (m, 2H), 8.25 (s, 1H), 8.00 (d, 1H), 7.70(m, 1H), 7.55-7.65 (m, 1H), 7.50 (s, 1H), 4.38 (m, 2H), 4.30 (m, 2H),4.10 (s, 3H), 3.90-4.00 (m, 1H), 3.30-3.40 (m, 2H), 3.23 (m, 2H),2.40-2.50 (m,2H), 2.20-2.35 (m, 4H), 1.80-1.95 (m, 2H):

MS (−ve ESI): 655 (M−H)⁻,

MS (+ve ESI): 657 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 17a, but startingwith cyclobutylamine (3.50 g, 49.3 mmol) yielded ethyl(cyclobutylamino)(oxo)acetate (assumed 8.43 g, quantitative yield):

¹H-NMR (CDCl₃): 7.10 (s, 1H), 4.30-4.40 (m, 2H), 3.10-3.20 (m, 1H),2.40-2.50 (m, 2H), 1.90-2.00 (m, 2H), 1.70-1.80 (m, 2H), 1.30-1.40 (m,3H):

MS (+ve ESI): 172 (M+H)⁺. p b) A solution of ethyl(cyclobutylamino)(oxo)acetate (8.43 g, 49.3 mmol) in tetrahydrofuran(100 ml) was added dropwise to a solution of lithium aluminium hydridein tetrahydrofuran (100 ml of a 1.0 N solution, 100 mmol) at ambienttemperature. The reaction was heated at reflux for 10 hours, cooled,diluted with tetrahydrofuran (200 ml) and quenched by addition of waterand 1.0 N aquoeous sodium hydroxide solution. The reaction was filteredand the filtrate evaporated in vacuo to yield 2-(cyclobutylamino)ethanol(5.50 g, 97% yield) as a colourless oil:

¹H-NMR (DMSO-d₆): 3.70-3.80 (m, 1H), 3.50-3.60 (m, 2H), 3.20-3.30 (m,1H), 2.60-2.70 (m, 2H), 2.30-2.40 (m, 2H), 1.60-1.70 (m, 4H).

c) An analogous reaction to that described in example 2d, but startingwith 2-(cyclobutylamino)(ethanol (518 mg, 4.50 mmol) yielded3-chloro-N-{5-[(7-{3-[cyclobutyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide (558 mg, 65% yield):

¹H-NMR DMSO-d₆): 11.00 (s, 1H), 9.70 (s, 1H), 8.80 (s, 1H), 8.60 (s,1H), 8.30 (dd, 1H), 8.20 (d, 1H), 8.10 (s, 1H), 8.00 (d, 1H), 7.80 (s,1H), 7.60 (d, 1H), 7.40-7.50 (m, 1H), 7.20 (s, 1H), 4.40 (br s, 1H),4.20 (t, 2H), 4.00 (s, 3H), 3.30-3.40 (m, 2H), 3.10-3.20 (m, 1H),2.60-2.70 (m, 2H), 1.90-2.10 (m, 4H), 1.70-1.80 (m, 2H), 1.40-1.50 (m,2H):

MS (−ve ESI): 575 (M−H)⁻,

MS (+ve ESI): 577 (M+H)⁺.

EXAMPLE 22 Preparation of Compound 22 in Table1-2-[(3-{4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyguinazolin-7-yl]oxy}propyl)(prop-2-yn-1-yl)amino]ethyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(795 mg, 1.42 mmol), initially yielded di-tert-butyl2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(prop-2-yn-1-yl)amino]ethylphosphate (452 mg, 42% yield) as a yellow gum:

¹H-NMR (DMSO d₆): 10.92 (s, 1H), 9.61 (s, 1H), 8.80 (s, 1H), 8.47 (s,1H), 8.28 (d, 1H), 8.21 (d, 1H), 8.10 (s, 1H), 8.01 (d, 1H), 7.85 (s,1H), 7.68 (d, 1H), 7.58 (t, 1H), 7.19 (s, 1H), 4.20 (t, 2H), 3.99 (s,3H), 3.92 (dd, 2H), 3.48 (s, 2H), 3.12 (s, 1H), 2.75 (m, 2H), 2.69 (m,2H), 1.95 (m, 2H), 1.39 (s, 18H)

MS (+ve ESI): 753 (M+H)⁺.

di-tert-butyl2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(prop-2-yn-1-yl)amino]ethylphosphate (445 mg, 0.59 mmol) was subjected to deprotection withhydrochloric acid (according to the method described in example 12 toyield the title compound (as the di-hydrochloride salt, 403 mg, 95%yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 12.07 (s, 1H), 11.10 (s, 1H), 8.88 (s, 1H), 8.81 (s,1H), 8.65 (s, 1H), 8.28 (s, 2H), 8.10 (s, 1H), 8.02 (d, 1H), 7.68 (d,1H), 7.57 (t, 1H), 7.49 (s, 1H), 4.30 (m, 6H), 4.08 (s, 3H), 3.89 (s,1H), 3.50 (m, 2H), 3.42 (m, 2H), 2.35 (m, 2H):

MS (+ve ESI): 641 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 17a, but startingwith propargylamine (2.75 g, 50 mmol) yielded ethyloxo(prop-2-yn-1-ylamino)acetate (assumed 7.75 g, quantitative yield):

¹H-NMR (CDCl₃): 7.37 (br s, 1H), 4.35 (dd, 2H), 4.15 (m, 2H), 2.31 (m,1H), 1.39 (t, 3H),

MS (+ve ESI): 156 (M+H)⁺.

b) An analogous reaction to that described in example 21b, but startingwith ethyl oxo(prop-2-yn-1-ylamino)acetate (7.75 g, 50 mmol) yielded2-(prop-2-yn-1-ylamino)ethanol (3.79 g, 77% yield) as a pale brown oil:

¹H-NMR (CDCl₃): 3.68 (m, 2H), 3.45 (s, 2H), 2.87 (m, 2H), 2.25 (s, 1H).

c) An analogous reaction to that described in example 2d, but startingwith 2-(prop-2-yn-1-ylamino)ethanol (540 mg, 5.45 mmol) yielded3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)(prop-2-yn-1-yl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyridin-2-yl}benzamide(945 mg, 85% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 10.30 (br s, 1H), 8.79 (s, 1H), 8.49 (s, 1H), 8.27 (d,1H), 8.20 (d, 1H), 8.10 (s, 1H), 8.00 (d,1H), 7.83 (s, 1H), 7.65 (d,1H), 7.53 (t, 1H), 7.18 (s, 1H), 4.40 (br s, 1H), 4.19 (m, 2H), 3.98 (s,3H), 3.48 (m, 2H), 3.43 (s, 2H), 3.06 (s, 1H), 2.65 (m, 2H), 2.52 (m,2H), 1.92 (m, 2H1):

MS (+ve ESI): 561 (M+H)⁺.

EXAMPLE 23 Preparation of Compound 23 in Table2-2-[(3-{[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclohexyl)amino]ethyldihydrogen phosphate

Dry 1H-tetrazole (113 mg, 1.62 mmol) and di-tert-butyldiethylphosphoramidite (201 mg, 0.81 mmol) were added to a solution of3-chloro-N-{5-[(7-{3-[cyclohexyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}-4-fluorobenzamide(126 mg, 0.57 mmol) in dimethylformamide (2 ml). The reaction wasstirred under an inert atmosphere at ambient temperature for 20 hours.The reaction mixture was diluted with ethyl acetate (50 ml) and washedwith three portions of aqueous sodium hydrogen carbonate. The organicswere dried over magnesium sulphate and concentrated to an oil. The oilwas dissolved in tetrahydrofuran (3 ml) and cooled to 0° C. Hydrogenperoxide (69 μl of a 30% w/v aqueous solution) was added and thereaction stirred for 48 hours at ambient temperature during which afurther portion of hydrogen peroxide (35 μl) was added. The reaction wasquenched with aqueous sodium metabisulphite, extracted intodichloromethane and dried over sodium sulphate. Purification by flashchromatography on alumina, eluting with 0-2% methanol indichloromethane, yielded a yellow solid after trituration with diethylether. The yellow solid (56 mg) was dissolved in 1,4 dioxane (2 ml) andhydrogen chloride (0.10 ml of a 4.0 N solution in 1,4-dioxane, 0.41mmol) was added dropwise to the solution. The reaction mixture wasstirred for 20 hours at ambient temperature. The reaction mixture wasdiluted with diethyl ether and the solid was collected by suctionfiltration and washed with diethyl ether to yield the title compound (asa solid dihydrochloride salt, 49 mg, 11% yield):

¹H-NMR (DMSO-d₆): 12.10 (s, 1H), 9.20 (s, 2H), 8.85 (s, 1H), 8.60 (s,1H), 8.20 (dd, 1H), 7.95-8.05 (m, 1H), 7.50-7.60 (m, 2H), 4.40 (t, 2H),4.20-4.30 (m, 2H), 4.00 (s, 3H), 3.20-3.45 (m, 4H), 2.20-2.40 (m, 2H),2.00-2.10 (m, 2H), 1.75-1.90 (m, 2H), 1.55-1.65 (m, 1H), 1.25-1.50 (m,4H), 1.10-1.20 (m, 1H):

³¹P-NMR {¹H} (DMSO- d₆): 0.55 (s, 1P):

MS (+ve ESI): 704.5/706.5 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[cyclohexyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}-4-fluorobenzamideused as starting material was obtained as follows:

a) 3-Chloro-4-fluorobenzoyl chloride (1.52 g, 7.88 mmol) was added to astirred solution of 2-amino-5-nitropyrimidine (1.00 g, 7.14 mmol) inanhydrous pyridine (20 ml) at ambient temperature and the reactionheated at reflux for 7 hours. The reaction was cooled to ambienttemperature, poured into water (200 ml) and allowed to stand for 18hours. The aqueous phase was extracted with dichloromethane (3×75 ml)and the combined organic extracts were washed with brine (2×100 ml) anddried (magnesium sulphate). Solvent evaporation in vacuo followed bypurification by flash chromatography on silica gel, eluting withdichloromethane: methanol (99:1 then 98:2) yielded3-chloro-4-fluoro-N-(5-nitropyrimidin-2-yl)benzamide (1.71 g, 81% yield)as abrown gum:

¹H-NMR (DMSO-d₆): 11.86 (br s, 1H), 9.44 (s, 2H), 8.20 (m, 1H), 7.98 (m,1H), 7.58 (t, 1H),

MS (−ve ESI): 295 (M−H)⁻,

MS (+ve ESI): 297 (M+H)⁺.

b) 10% Platinum on carbon (149 mg) was added to a stirred suspension of3-chloro-4-fluoro-N-(5-nitropyrimidin-2-yl)benzamide (743 mg, 2.51 mmol)in ethanol (50 ml) at ambient temperature and the reaction stirred for18 hours under an atmosphere of hydrogen. The reaction was filteredthrough a pad of celite and the solvent evaporated in vacuo to yield asolid which was taken up in ethyl acetate: ethanol (4:1) and filtered(0.45 μM PTFE filter). The solvent was evaporated to yieldN-(5-aminopyrimidin-2-yl)-3-chloro-4-fluorobenzamide (5.77 g, 99% yield)as a brown solid:

¹H-NMR (DMSO-d₆): 10.64 (br s, 1H), 8.15 (m, 1H), 8.07 (s, 2H), 7.94 (m,1H), 7.54 (t, 1H), 5.41 (s, 2H):

MS (−ve ESI): 265 (M−H)⁻,

MS (+ve ESI): 267 (M+H)⁺.

c) Hydrogen chloride (3.0 ml of a 4.0 N solution in dioxane, 12.0 mmol)was added to a stirred solution of7-(benzyloxy)-4-chloro-6-methoxyquinazoline (3.40 g, 11.25 mmol) andN-(5-aminopyrimidin-2-yl)-3-chloro-4-fluorobenzamide (3.00 g, 11.25mmol) in dimethylacetaride (50 ml) and the reaction heated at 50° C. for3.5 hours. The reaction was allowed to cool to ambient temperature andthe precipitated solid was collected by suction filtration. Washing ofthe solid with diethyl ether followed by drying in vacuo yieldedN-(5-{[7-(benzyloxy)-6-methoxyquinazolin-4-yl]amino}pyrimidin-2-yl)-3-chloro-4-fluorobenzamide(5.33 g, 79% yield) as a cream solid:

¹H-NMR (DMSO-d₆): 11.80 (br s, 1H), 11.27 (br s, 1H), 9.11 (s, 2H), 8.85(s, 1H), 8.42 (s, 1H), 8.10 (m, 1H), 8.00 (m, 1H), 7.37-7.60 (m, 7H),5.34 (s, 2H), 4.03 (s, 3H):

MS (−ve ESI): 529 (M−H)⁻,

MS (+ve ESI): 531 (M+H)⁺.

d)N-(5-{[7-(benzyloxy)-6-methoxyquinazolin-4-yl]amino}pyrimidin-2-yl)-3-chloro-4-fluorobenzamide(5.33 g, 8.83 mmol) was added to trifluoroacetic acid (50 ml) and thereaction heated at reflux for 2 hours. The reaction was cooled toambient temperature, the volatiles were evaporated in vacuo and theresultant brown oil was azeotroped with dichloromethane (2×50 ml).Addition of diethyl ether (50 ml) caused the formation of a precipitatewhich was collected by suction filtration and dried in vacuo to yield3-chloro-4-fluro-N-{5-[(7-hydroxy-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide(trifluoroacetate salt, 4.73 g, 97% yield) as an off-white solid:

¹H-NMR (DMSO-d₆): 11.27 (br s, 1H), 9.03 (s, 2H), 8.81 (s, 1H), 8.19 (s,1H), 8.00 (m, 2H), 7.57 (t, 1H), 7.21 (s, 1H), 4.00 (s, 3H):

MS (−ve ESI): 439 (M−H)⁻,

MS (+ve ESI): 441 (M+H)⁺.

e) A mixture of3-chloro-4-fluoro-N-{5-[(7-hydroxy-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide(750 mg, 1.35 mmol), 1,3-dibromopropane (327 mg, 1.62 mmol) andpotassium carbonate (411 mg, 2.98 mmol) in dimethylacetamide (3 ml) werestirred at ambient temperature for 20 hours beforeN-cyclohexyl(ethanol)amine (965 mg, 6.75 mmol) was added to thesolution. The reaction mixture was stirred at ambient temperature for 48hours then concentrated under reduced pressure. Purification by flashchromatography on silica gel, eluting with dichloromethane : methanol:saturated ammonia (93:5:2 to 78:20:2) yielded3-chloro-N-{5-[(7-{3-[cyclohexyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}-4-fluorobenzamide(126 mg, 15% yield) as a 5 yellow solid:

¹H-NMR (DMSO-d₆): 11.10 (s, 1H), 9.80 (s, 1H), 9.15 (s, 2H), 8.45 (s,1H), 8.20 (d, 2H), 7.95-8.05 (m, 1H), 7.80 (s, 1H), 7.50-7.60 (m, 1H),7.20 (s, 1H), 4.25 (t, 2H), 4.00 (s, 3H), 3.30-3.50 (m, 4H), 2.50-2.80(m, 4H), 1.80-2.00 (m, 2H), 1.50-1.75 (m, 4), 1.10-1.30 (m, 5H):

MS (−ve ESI): 622 (M−H)⁻,

MS (+ve ESI): 624 (M+H)⁺.

EXAMPLE 24 Preparation of Compound 24 in Table2-2-[(3-{[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]ethyldihydrogen phosphate

Dry 1H-tetrazole (1.34 g, 19.21 mmol) and di-tert-butyldiethylphosphoramidite (2.95 g, 11.85 mmol) were added in 3 aliquots toa solution of3-chloro-N-{5-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4yl)amino]pyrimidin-2-yl}-4-fluorobenzamide(1.5 g, 2.63 mmol) in dimethylacetamide (60 ml). The reaction wasstirred under an inert atmosphere at ambient temperature for 72 hours.The reaction mixture was diluted with ethyl acetate (200 ml) and washedwith three portions of aqueous sodium hydrogen carbonate. The organicswere dried over sodium sulphate and concentrated to an oil. The oil wasdissolved in tetrahydrofuran (25 ml) and cooled to 0° C. Hydrogenperoxide (599 μl of a 30% w/v aqueous solution) was added and thereaction stirred for 20 hours at ambient temperature during which afurther portion of hydrogen peroxide (300 μl) was added. The reactionwas quenched at 0° C. with aqueous sodium metabisulphite, extracted intoethyl acetate, dichloromethane and methanol and dried over magnesiumsulphate. Purification by flash chromatography on alumina, eluting with0-5% methanol in dichloromethane yielded a yellow foam. The yellow foam(859 mg) was dissolved in 1,4 dioxane (50 ml) and hydrogen chloride (1.7ml of a 4.0 N solution in 1,4-dioxane, 6.78 mmol) was added dropwise tothe solution. The reaction mixture was stirred for 20 hours at ambienttemperature. The reaction mixture was diluted with diethyl ether (300ml) the solid collected by suction filtration and washed with diethylether to yield the title compound (as a solid dihydrochloride salt, 799mg, 42% yield):

¹H-NMR (DMSO-d₆): 12.30 (s, 1H), 11.20 (s, 1H), 9.20 (s, 2H), 8.90 (s,1H), 8.20 (dd, 1H), 7.95-8.05 (m, 1H), 7.50-7.60 (m, 1H), 7.40 (s, 1H),4.20-4.40 (t, 4H), 4.00 (s, 3H), 3.50-3.60 (m, 2H), 3.20-3.20 (m, 4H),2.20-2.40 (m, 2H), 1.30 (t, 3H):

³¹P-NMR{¹H} (DMSO-d₆): −0.23 (s, 1P):

MS (+ve ESI): 650, 652 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[ethyl(2-hydroxyethyl)aminopropoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}-4-fluorobenzamideused as starting material was obtained as follows:

A mixture3-chloro-4-fluoro-N-{5-[(7-hydroxy-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide(8 g, 14.4 mmol), 1-bromo-3-chloropropane (2.49 g, 15.9 mmol) andcaesium carbonate (9.38 g, 28.8 mmol) in dimethylformamide (80 ml) werestirred at ambient temperature for 20 hours before N-ethyl(ethanol)amine(6.4 g, 72 mmol) was added to the solution. The reaction mixture wasstirred at 70° C. for 48 hours then concentrated under reduced pressure.Purification by flash chromatography on silica gel, eluting with 1-20%methanol in dichloromethane containing 2% concentrated ammonia, yielded3-chloro-N-{5-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}-4-fluorobenzamide(2.5 g, 30% yield) as a yellow solid:

¹H-NMR (DMSO-d₆): 11.10 (s, 1H), 9.75 (s, 1H), 9.15 (s, 2H), 8.45 (s,1H), 8.20 (dd, 1H), 7.95-8.05 (m, 1H), 7.80 (s, 1H), 7.50-7.60 (m, 1H),7.20 (s, 1H), 4.25 (br s, 1H), 4.20 (t, 2H), 4.00 (s, 3H), 3.40-3.50 (m,2H), 2.50-2.65 (m, 6H), 1.80-2.00 (m, 2H), 0.95 (t, 3H),

MS (+ve ESI): 570, 572 (M+H)⁺,

MS (−ve ESI): 568, 570 (M−H)⁻.

EXAMPLE 25 Preparation of Compound 25 in Table2-3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyguinazolin-7-yl]oxy}propyldihydrogen phosphate

An analogous reaction to that described in example 9, but starting with3-chloro-N-(5-{[7-(3-hydroxypropoxy)-6-methoxyquinazolin-4-yl]amino}pyrimidin-2-yl)benzamide(100 mg, 0.21 mmol) yielded the title compound as a pale yellow solid(66 mg, 56% yield):

¹H-NMR (DMSO-d₆): 12.10 (s, 1H), 11.26 (s, 1H), 9.13 (s, 2H), 8.89 (s,1H), 8.54 (s, 1H), 8.00 (s, 1H), 7.92 (d, 1H), 7.68 (m, 1H), 7.54 (t,1H), 7.41 (s, 1H), 4.28 (t, 2H), 4.03 (s, 3H), 4.02 (q, 2H), 2.15 (m,2H):

MS (+ve ESI): 561 (M+H)⁺.

3-chloro-N-(5-{[7-(3-hydroxypropoxy)-6-methoxyquinazolin-4-yl]amino}pyrimidin-2-yl)benzamideused as the starting material was obtained in an analogous reaction tothat described in example 23e, but starting with 3-bromopropanol (154mg, 1.10 mmol) and3-chloro-N-{5-[(7-hydroxy-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide (520 mg, 1 mmol—see WO 01/21597) but no amine was added. Thereaction yielded the title compound as an off-white solid (151 mg, 31%yield):

¹H-NMR (DMSO-d₆): 11.11 (s, 1H), 9.72 (s, 1H), 9.11 (s, 2H), 8.47 (s,1H), 8.02 (s, 1H), 7.93 (d, 1H), 7.79 (s, 1H), 7.65 (d, 1H), 7.53 (t,1H), 7.21 (s, 1H), 4.56 (t, 1H), 4.20 (t, 2H), 3.96 (s, 3H), 3.58 (q,2H), 1.94 (m, 2H):

MS (+ve ESI): 481 (M+H)⁺.

EXAMPLE 26 Preparation of Compound 26 in Table2-1-[3-({4-[(2-{[(3-chloro-4-fluorophenyl)amino]methyl}pyrimidin-5-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yldihydrogen phosphate

An analogous reaction to that described in example 9, but starting with1-[3-({4-[(2-{[(3-chloro-4-fluorophenyl)amino]methyl}pyrimidin-5-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-ol(500 mg, 0.88 mmol) yielded the title compound (121 mg, 21% yield):

¹H-NMR (DMSO-d₆): 12.20 (s, 1H), 10.69 (s, 1H), 9.27 (s, 2H), 9.00 (s,1H), 8.63 (s, 1H), 7.54 (s, 1H), 7.11 (dd, 1H), 6.80 (dd, 1H), 6.65 (m,1H), 5.22 (br s, 5H), 4.51 (s, 1H), 4.33 (t, 2H), 4.07 (s, 3H),3.58-3.39 (m, 2H), 3.30-3.09 (m, 4H), 2.35 (m, 2H), 2.17 (m, 2H), 2.00(m, 2H):

³¹P-NMR {¹H} (DMSO-d₆): −1.0 (s, 1P):

MS (−ve ESI): 646/648 (M−H)⁻,

MS (+ve ESI): 648/650 (M+H)⁺.

1-[3-({4-[(2-{[(3-chloro-4-fluorophenyl)amino]methyl}pyrimidin-5-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-olused as starting material was obtained as follows:

a) Sodium hydride (1.20 g, 31.65 mmol) was added at ambient temperatureto a solution of 2-(diethoxymethyl)pyrimidin-5-amine (1.87 g, 9.49 mmol,see-WO 01/21597) in tetrahydrofuran (60 ml). The reaction mixture wasstirred for 10 minutes before the addition of4-chloro-6-methoxy-7-(3-chloropropoxy)quinazoline (4.00 g, 13.93 mmol).The reaction mixture was heated to reflux for 3 hours, cooled to ambienttemperature and diluted with ethyl acetate (80 ml). The resultantprecipitate was removed by filtration through celite and the filtrateconcentrated to a brown powder. This was dissolved in dichloromethane:methanol (9:1) and purified by flash chromatography on silica gel.Elution with dichloromethane: methanol (9:1), afforded7-(3-chloropropoxy)-N-[2-(diethoxymethyl)pyrimidin-5-yl]-6-methoxyquinazolin-4-amineas an orange powder (5.47 g, 88% yield, 74% pure), used crude in thenext reaction.

MS (+ve ESI) : 448 (M+H)⁺.

b)7-(3-Chloropropoxy)-N-[2-(diethoxymethyl)pyrimidin-5-yl]-6-methoxyquinazolin-4-amine(4.62 g, 10.3 mmol) was dissolved in a mixture of dichloromethane :trifluoroacetic acid: water (6:1:1, 200 ml) and stirred at ambienttemperature for 7 hours. The dichloromethane was removed and the residuesuspended in diethyl ether (500 ml), filtered and dried in a vacuum ovenfor 24 hours to afford5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}pyrimidine-2-carbaldehydeas the trifluoroacetic acid salt (4.64 g, 92% yield), used crude in thenext reaction.

c) Sodium cyanoborohydride (386 mg, 6.15 mmol) and acetic acid (586 μl,10.3 mmol) were added to a solution of5-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}pyrimidine-2-carbaldehyde(2.50 g, 5.12 mmol) and 4-fluoro-3-chloroaniline (3.73 g, 25.6 mmol) inmethanol (25 ml) under nitrogen. The reaction was stirred at ambienttemperature for 2 hours, diluted with diethyl ether (180 ml) and theresultant solid collected by filtration. The solid was washed withdiethyl ether and dried in a vacuum oven to giveN-(2-{[(3-chloro-4-fluorophenyl)amino]methyl}pyrimidin-5-yl)-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amineas a yellow powder (1.81 g, 70% yield). The product was used directly inthe next reaction.

d) An analogous reaction to that described in example 2d was performed,but starting with 4-hydroxypiperidine (1.00 g, 9.95 mmol) andN-(2-{[(3-chloro-4-fluorophenyl)amino]methyl}pyrimidin-5-yl)-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine(1.0 g, 2.0 mmol). Purification by flash chromatography, eluting withdichloromethane:methanol (9:1) followed by increased polarity todichloromethane:methanol:ammonia (9:1:0.6) yielded1-[3-({4-[(2-{[(3-chloro-4-fluorophenyl)amino]methyl}pyrimidin-5-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-olas a pale yellow solid (700 mg, 62% yield):

¹H-NMR (DMSO-d₆): 9.73 (s, 1H), 9.20 (s, 2H), 8.50 (s, 1H), 7.80 (s,1H), 7.22 (s, 1H), 7.10 (dd, 1H), 6.78 (dd, 1H), 6.64 (m, 1H), 6.48 (dd,1H), 4.50 (d, 1H), 4.44 (d, 2H), 4.18 (t, 2H), 3.97 (s, 3H), 3.44 (m,1H), 2.73 (m, 2H), 2.42 (m, 2H), 2.05-1.91 (m, 4H), 1.71 (m, 2H), 1.41(m, 2H):

¹⁹F-NMR (DMSO-d₆): −134.4 (m):

MS (−ve ESI): 566, 568 (M−H)⁻,

MS (+ve ESI): 568, 570 (M+H)⁺.

EXAMPLE 27 Preparation of Compound 27 in Table2-3-[(3-{[4-({2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyldihydrogen phosphate

An analogous reaction to that described in example 9, but starting with3-[(3-{[4-({2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutan-1-ol(1.14 g, 2.00 mmol) yielded the title compound as a pale yellow solid(149 mg, 17% yield):

¹H-NMR (DMSO-d₆): 9.73 (s, 1H), 8.98 (s, 2H), 8.43 (s, 1H), 7.82 (s,1H), 7.74 (m, 1H), 7.53 (m, 1H), 7.46 (t, 1H), 7.25 (s, 1H), 5.41 (s,2H), 4.24 (t, 2H), 3.99 (s, 3H), 3.92 (m, 2H), 3.0 (t, 2H), 2.21 (m,2H), 1.85 (t, 2H), 1.31 (s, 6H):

MS (+ve ESI): 651 (M+H)⁺.

3-[(3-{[4-({2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutan-1-ol,used as the starting material, was obtained as follows:

a) 2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-amine (2.54 g, 10.0 mmol,see WO 01/21597) and 4-chloro-6-methoxy-7-(3-chloroxypropoxy)quinazoline(2.87 g, 10 mmol) were dissolved in dimethylacetamide (60 nm) and warmedto 40° C. Hydrogen chloride (4 N solution in 1,4 dioxane, 2.5 ml, 10mmol) was added slowly and the reaction heated at 70° C. for 30 minutes.The reaction was cooled, diluted with ether and the resultantprecipitate collected by filtration and washed with diethyl ether. Thesolid was triturated with acetonitrile to affordN-{2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-yl)-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (di-hydrochloride salt)as an off-white solid (4.88 g, 90% yield):

¹H-NMR (DMSO-d₆): 8.96 (s, 2H), 8.82 (s, 1H), 8.40 (s, 1H), 7.70 (m,1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.38 (s, 1H), 5.41 (s, 2H), 4.30 (t,2H), 4.02 (s, 3H), 3.82 (t, 2H), 2.28 )t, 2H),

MS (+ve ESI): 504 (M+H)⁺.

b) An analogous reaction to that described in example 2d, but startingwithN-{2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-yl}-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine(2.7 g, 5.00 mmol) and 3-amino-3-methylbutanol (2.57 g, 25.0 mmol). Thereaction yielded3-[(3-{[4-({2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutan-1-olas a colourless solid (2.22 g, 78% yield):

¹H-NMR (DMSO-d₆): 9.65 (s, 1H), 8.97 (s, 2H), 8.47 (s, 2H), 7.79 (s,1H), 7.72 (m, 1H), 7.51 (m, 1H), 7.45 (t, 1H), 7.21 (s, 1H), 5.41 (s,2H), 4.21 (t, 2H), 3.98 (s, 3H), 3.82 (t, 2H), 2.69 (t, 2H), 1.90 (t,2H), 1.53 (t, 2H), 1.04 (s, 6H):

MS (+ve ESI):571(M+H)⁺.

EXAMPLE 28 Preparation of Compound 28 in Table2-2-[(3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(2,2-dimethylpropyl)amino]ethyldihydrogen phosphate

An analogous reaction to that described in example 12, but starting with3-chloro-N-{5-[(7-(3-[(2-hydroxyethyl)(2,2-dimethylpropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide (600 mg, 1.01 mmol), initiallyyielded di-tert-butyl2-[(3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(2,2-dimethylpropyl)amino]ethylphosphate (610 mg, 77% yield) as a pale yellow solid:

¹H-NMR (DMSO d₆): 11.09 (s, 1H), 9.74 (s, 1H), 9.12 (s, 2H), 8.50 (s,1H), 8.03 (s, 1H), 7.95 (d, 1H), 7.82 (s, 1H), 7.69 (d, 1H), 7.57 (t,1H), 7.20 (s, 1H), 4.20 (t, 2H), 3.98 (s, 3H), 3.88 (dd, 2H), 2.70 (m,4H), 2.27 (s, 2H), 1.93 (m, 2H), 1.38 (s, 18H), 0.84 (s, 9H):

MS (+ve ESI): 786 (+H)⁺.

di-tert-butyl2-[(3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(2,2-dimethylpropyl)amino]ethyl phosphate (600 mg, 0.76 mmol) wassubjected to deprotection with hydrochloric acid (according to themethod described in example 12 to yield the title compound (as thetri-hydrochloride salt, 600 mg, quantitative yield) as a pale yellowsolid:

¹H-NMR (DMSO d₆): 12.30 (s, 1H), 11.27 (s, 1H), 9.18 (s, 2H), 8.90 (s,1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.95 (d, 1H), 7.71 (d, 1H), 7.58 (t,1H), 7.52 (s, 1H), 4.35 (m, 4H), 4.05 (s, 3H), 3.51 (m, 2H), 3.40 (m,2H), 3.19 (s, 2H), 2.50 (m, 2H), 1.13 (s, 9H):

MS (+ve ESI): 674 (M+H)⁺.

3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)(2,2-dimethylpropyl)amino]propoxy}-6-methoxyquinaolin-4-yl)amino]pyrimidin-2-yl}benzamide,used as the starting material, was obtained as follows:

a) An analogous reaction to that described in example 2d, but startingwith 2-[(2,2-dimethylpropyl)amino]ethanol (1.10 mg, 12.0 mmol) yielded3-chloro-N-{5-[(7-{3-[(2-hydroxyethyl)(2,2-dimethylpropyl)amino]propoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide(663 mg, 28% yield) as an off-white solid:

¹H-NMR (DMSO d₆): 11.10 (br s, 1H), 9.75 (br s, 1H), 9.12 (s, 2H), 8.50(s, 1H), 8.02 (s, 1H), 7.93 (d, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.56(t, 1H), 7.20 (s, 1H), 4.29 (t, 1H), 4.19 (t, 2H), 3.98 (s, 3H), 3.46(m, 2H), 2.68 (t, 2H), 2.50 (t, 2H1), 2.20 (s, 2H), 1.92 (m, 2H), 0.82(s, 9H):

MS (+ve ESI): 594 (M+H)⁺.

EXAMPLE 29 Preparation of Compound 29 in Table 3-[2-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)cyclopropyl]methyldihydrogen phosphate

An analogous reaction to that described in example 9, but starting with3-chloro-4-fluoro-N-{5-[(7-{[2-(hydroxymethyl)cyclopropyl]methoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide(234 mg, 0.44 mmol) yielded the title compound as a pale orange solid(49 mg, 58% yield):

¹H-NMR (DMSO-d₆): 11.30 (s, 1H), 9.15 (s, 2H), 8.75 (s, 1H), 8.20 (d,1H), 8.05 (m, 2H), 7.70 (t, 1H), 7.25 (s, 1H), 4.20 (m, 1H), 4.10-4.00(m, 4H), 3.90 (m, 2H), 1.40-1.00 (m, 2H), 0.70 (m 2H):

MS (+ve ESI): 605 (M+H)⁺.

3-chloro-4-fluoro-N-{5-[(7-{[2-(hydroxymethyl)cyclopropyl]methoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzanide,used as the starting material was obtained as follows:

a)3-chloro-4-fluoro-N-{5-[(7-hydroxy-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide(3.50 g, 6.31 mmol), ethyl 2-(bromomethyl)cyclopropykcarboxylate (1.55g, 7.49 mmol, see WO 92/04339) and potassium carbonate (4.12 g, 33.55mmol) were combined in dimethylacetamide and heated to 60° C. for 18hours. The reaction mixture was poured into water (400 ml) and theresultant precipitate filtered, dried and washed with diethyl ether toafford ethyl2-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)cyclopropylcarboxylateas a beige solid (2.75 g, 77% yield):

MS (+ve ESI): 565 (M+H)⁺.

b) A solution of lithium aluminium hydride (5.5 ml, 1M solution intetrahydrofuran) in tetrahydrofaran (60 ml) was cooled to 0° C. and asolution of ethyl2-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)cyclopropylcarboxylate(1.56 g, 2.75 mmol) in tetrahydrofuran (20 ml) was added slowly. Thesolution was stirred at 0° C. for 3 hours and further portions oflithium aluminium hydride (3×2.75 ml) were added at 0° C. at 18, 28 and36 hours with wanning to ambient temperature between each addition. Thereaction mixture was cooled to 0° C. and hydrochloric acid (15 ml, 1 Nsolution in water) added slowly. Water (200 ml) was added and thereaction extracted with ethyl acetate (3×200 ml). The organics werecombined, dried (magnesium sulphate) and concentrated (<20° C.) toafford a yellow solid. Trituration with diethyl ether afforded3-chloro-4-fluoro-N-{5-[(7-{[2-(hydroxymethyl)cyclopropyl]methoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamideas a yellow solid (726 mg, 50% yield):

¹H-NMR (DMSO-d₆): 9.80 (s, 1H), 9.20 (s, 2H), 8.50 (s, 1H), 8.20 (d,1H), 8.05 (m, 2H), 7.81 (s, 1H), 7.65 (t, 1H), 7.25 (s, 1H), 4.50 (t,1H), 4.20-3.80 (m, 2H), 3.40-3.20 (m, 2H), 1.40-1.00 (m, 2H), 0.61 (m2H):

MS (+ve ESI): 525 (M+H)⁺.

EXAMPLE 30 Preparation of Compound 30 in Table3-2-[4-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)piperidin-1-yl]ethyldihydrogen phosphate

A solution of3-chloro-4-fluoro-N-{5-[(7-{[1-(2-hydroxyethyl)piperidin-4-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide(79 mg, 0.13 mmol) in dimethylformamide (2 ml) was reacted with 1-Htetrazole (41 mg, 0.58 mmol) and dibenzyl diethylphosphoramidite (60 μl,0.20 mmol) and stirred at ambient temperature for 18 hours. Furtherportions of dibenzyl diethylphosphoramidite (100 μl) were added after 2hours and 5 hours. The reaction mixture was cooled to −50° C. and3-chloroperoxybenzoic acid (81 mg, 0.46 mmol) was added and the reactionmixture warmed to 0° C. A further portion of 3-chloroperoxybenzoic acid(60 mg) was added at −50° C. and the solution was stirred for 4 hoursthen cooled to 0° C. A solution of sodium metabisulphite (0.53 N aqueoussolution) was added and the reaction was warmed to ambient temperatureover 15 minutes then extracted with dichloromethane. The combinedorganics were dried (magnesium sulphate), filtered and concentratedunder reduced pressure to yield the crude phosphate ester as a viscous,yellow oil. Purification by flash chromatography on silica gel, elutingwith dichloromethane: methanol: 7.0 N ammonia in methanol (9:1:0 to9:1:0.8) yielded dibenzyl2-[4-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6methoxyquinazolin-7-yl]oxy}methyl)piperidin-1-yl]ethyl phosphate as ayellow oil (41 mg, 46% yield):

MS (+ve ESI): 842 (M+H)⁺.

Dibenzyl2-[4-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6methoxyquinazolin-7-yl]oxy}methyl)piperidin-1-yl]ethyl phosphate (41 mg,0.048 mmol) was dissolved in dichloromethane and cooled to −78° C.Bromotrimethylsilane (70 μl, 0.05 mmol) was added and the solutionallowed to warm to ambient temperature and stirred for 1 hour. Methanol(3 ml) was added and the reaction concentrated, redissolved in methanoland evaporated to dryness. The residue was triturated with diethyl etherand filtered under nitrogen to yield the title compound as a yellowhydrobromide salt (41 mg, 98% yield):

¹H-NMR (DMSO-d₆): 9.20 (s, 2H), 8.80 (s, 1H), 8.55 (s, 1H), 8.25 (s,1H), 8.20 (m, 1H), 8.05 (m, 1H), 7.51 (t, 1H), 7.41 (s, 1H), 4.30 (m,2H), 4.20 (m, 2H), 4.05 (s, 3H), 3.60 (m, 2H), 3.41 (t, 2H), 3.20 (t,2H), 2.35 (m, 1H), 2.25 (m, 2H), 1.90-1.70 (m, 2H):

MS (−ve ESI): 660 (M−H)⁻.

3-chloro-4-fluoro-N-{5-[(7-{[1-(2-hydroxyethyl)piperidin-4-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamideused as the starting material was obtained as follows:

a)3-chloro-4-fluoro-N-{5-[(7-hydroxy-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamide(3.85 g, 6.94 mmol), tert-butyl4-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-l-carboxylate (3.16g, 8.55 mmol see-patent WO 02/00649) and potassium carbonate (4.2 g,30.4 mmol) were dissolved in dimethylacetamide (50 ml) and stirred at60° C. for 18 hours. The reaction mixture was cooled, poured into water(100 ml) and the resultant precipitate isolated. This was dissolved in amixture of dichloromethane : trifluoroacetic acid (2:1, 30 ml) andstirred at ambient temperature for 5 hours. The reaction mixture wasconcentrated, toluene added and reconcentrated. The resultant solid wastriturated with ether, filtered and dried to yield3-chloro-4-fluoro-N-(5-{[6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yl]amino}pyrimidin-2-yl)benzamidedi-trifluoroacetate as a beige solid (4.6 g, 86% yield):

MS (+ve ESI): 538 (M+H)⁺.

b)3-chloro-4-fluoro-N-(5-{[6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yl]amino}pyrimidin-2-yl)benzamidedi-trifluoroacetate (4.6 g, 6.0 mmol), triethylamine (5 ml, 26.6 mmol)and 2-bromoethanol (2.20 ml, 31.0 mmol) were dissolved indiimethylformamide (100 ml) and heated at 60° C. for 18 hours. Thereaction mixture was cooled and concentrated. Purification by flashchromatography on silica gel, eluting with dichloromethane : methanol(4:1) followed by increased polarity to dichloromethane:methanol:ammonia (4:1:0.1) yielded 3-chloro-4-fluoro-N-{5-[(7-{[1-(2-droxyethyl)piperidin-4-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]pyrimidin-2-yl}benzamideas a beige solid (1.7 g, 48% yield):

¹H-NMR (DMSO-d₆): 9.80 (s, 1H), 9.15 (s, 2H), 8.80 (s, 1H), 8.20 (m,1H), 8.00 (m,1H), 7.80 (s, 1H), 7.60 (t, 1H), 4.20 (s, 1H), 4.05 (m,5H), 3.65 (m, 2H), 3.15 (m, 2H), 2.40 (m, 2H), 2.25-2.00 (m, 2H),1.90-1.70 (m, 3H), 1.55 (m, 2H):

MS (−ve ESI): 580 (M−H)⁻.

1. A compound of formula (I):

wherein A is 6-membered heteroaryl containing a nitrogen atom andoptionally containing one or two further nitrogen atoms; X is O, S,S(O), S(O)₂ or NR¹⁴; m is 0, 1, 2, 3 or 4; Y is a group selected from O,NR⁵CO, CONR⁵, CR⁶R⁷CONR⁵ and CR⁶R⁷NR⁵; Z is a group selected from—NR¹R², phosphonooxy, C₃₋₆cycloalkyl which C₃₋₆cycloalkyl is substitutedby phosphonooxy or C₁₋₄alkyl substituted by phosphonooxy, and a 4- to7-membered ring linked via a carbon atom containing a nitrogen atom andoptionally containing a further nitrogen atom, which ring may besaturated, unsaturated or partially saturated which ring is substitutedon carbon or nitrogen by phosphonooxy or C₁₋₄alkyl (substituted byphosphonooxy) and which ring is optionally further substituted on carbonor nitrogen by 1, 2 or 3 halo or C₁₋₄alkyl groups; R¹ is a groupselected from —COR⁸, —CONR⁸R⁹ and C₁₋₆alkyl which C₁₋₆alkyl issubstituted by phosphonooxy and optionally further substituted by 1 or 2halo or methoxy groups; R² is a group selected from hydrogen, —COR¹⁰,—CONR¹⁰R¹¹and C₁₋₆alkyl which C₁₋₆alkyl is optionally substituted by 1,2 or 3 halo or C₁₋₄alkoxy groups, —S(O)_(p)R¹¹ (where p is 0, 1 or 2) orphosphonooxy, or R² is a group selected from C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl; or R¹ and R² together withthe nitrogen to which they are attached form a 4- to 7-membered ringoptionally containing a further nitrogen atom which ring may besaturated, unsaturated or partially saturated which ring is substitutedon carbon or nitrogen by a group selected from phosphonooxy andC₁₋₄alkyl substituted by phosphonooxy or —NR⁸R⁹, and which ring isoptionally further substituted on carbon or nitrogen by 1, 2 or 3 haloor C₁₋₄alkyl groups; R³ is a group selected from hydrogen, halo, cyano,nitro, C₁₋₆alkoxy, C₁₋₆alkyl, —OR¹², —CHR¹²R¹³, —OC(O)R¹², —C(O)R¹²,—NR¹²C(O)R¹³, —C(O)NR¹²R¹³, —NR¹²SO₂R¹³ and —NR¹²R¹³; R⁴ is hydrogen ora group selected from C₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄alkyl, aryland arylC₁₋₄alkyl which group is optionally substituted by 1, 2 or 3rubstitutents substituents selected from halo, methyl, ethyl,cyclopropyl and ethynyl; R⁵ is a group selected from hydrogen,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl anC₃₋₆cycloalkylC₁₋₄alkyl; R⁶ and R⁷ are independently selected fromhydrogen, halo, C₁₄alkyl, C₃₋₆cycloalkyl, hydroxy and C₁₋₄alkoxy; R⁸ isC₁₋₄alkyl substituted by phosphonooxy and optionally further substitutedby 1 or 2 halo or methoxy groups; R⁹ is selected from hydrogen andC₁₋₄alkyl; R¹⁰ is selected from hydrogen and C₁₋₄alkyl which C₁₋₄alkylis optionally substituted by halo, C₁₋₄alkoxy, S(O)_(q) (where q is 0, 1or 2) or phosphonooxy; R¹¹, R¹², R¹³ and R¹⁴ are independently selectedfrom hydrogen, C₁₋₄alkyl and heterocyclyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1 wherein A isa group of formula (a), (b), (c) or (d):

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the Y group of formula (I); or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 2 wherein A is a group of formula (b) or (d) as defined in claim2; or a pharmaceutically acceptable salt thereof.
 4. A compoundaccording to claim 1 wherein X is NH; or a pharmaceutically acceptablesalt thereof.
 5. A compound according to claim 1 wherein Z is a groupselected from —NR¹R², phosphonooxy, cyclopropyl which cyclopropyl issubstituted by C₁₋₄alkyl substituted by phosphonooxy, and a piperidineor piperazine ring linked via carbon which ring is substituted on carbonor nitrogen by phosphonooxy or C₁₋₄alkyl substituted by phosphonooxy; ora pharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1 wherein R¹ is C₁₋₅alkyl substituted by phosphonooxy and R² ishydrogen, C₁₋₅alkyl, C₂₋₄alkynyl or C₃₋₆cycloalkyl; or apharmaceutically acceptable salt thereof.
 7. A compound according toclaim 1 wherein R¹ and R² together with the nitrogen to which they areattached form a piperidine, pyrrolidine or piperazine ring which issubstituted on carbon or nitrogen by a group selected from phosphonooxy,phosphonooxymethyl and 2-phosphonooxyethyl and where the ring isoptionally further substituted on carbon or nitrogen by 1 or 2 methyl.8. A compound according to claim 1 wherein R³ is methoxy or hydrogen; ora pharmaceutically acceptable salt thereof.
 9. A compound according toclaim 1 wherein R⁴ is phenyl or benzyl optionally substituted by 1 or 2of fluoro or chloro; or a pharmaceutically acceptable salt thereof. 10.A compound selected from:3-[(3-{[4-({6-[(3-chlorobenzyl)oxy]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyldihydrogen phosphate;3-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyldihydrogen phosphate; 2-[(3-{[4-({6-[(3chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]ethyldihydrogen phosphate;2-[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-2-yl]ethyldihydrogen phosphate;[(2R)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)pyrrolidin-2-yl]methyldihydrogen phosphate;2-[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl]ethyldihydrogen phosphate;2-[ethyl(3-{[4-({6-[(3-fluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]ethyldihydrogen phosphate;2-[(3-{[4-({6-[(3,4-difluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isopropyl)amino]ethyldihydrogen phosphate;(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yldihydrogen phosphate;4-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}butyldihydrogen phosphate;2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(methyl)amino]ethyldihydrogen phosphate;[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-2-yl]methyldihydrogen phosphate;2-[(5-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}pentyl)(ethyl)amino]ethyldihydrogen phosphate;4-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]butyldihydrogen phosphate;2-[(3-{[4-({6-[(3-fluorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(methyl)amino]ethyldihydrogen phosphate;2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(isobutyl)amino]ethyldihydrogen phosphate;2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclopropyl)amino]ethyldihydrogen phosphate;[1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperidin-4-yl]methyldihydrogen phosphate;2-[4-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)piperazin-1-yl]ethyldihydrogen phosphate;[(2S)-1-(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)pyrrolidin-2-yl]methyldihydrogen phosphate;2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclobutyl)amino]ethyldihydrogen phosphate;2-[(3-{[4-({6-[(3-chlorobenzoyl)amino]pyridin-3-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(prop-2-yn-1-yl)amino]ethyldihydrogen phosphate;2-[(3-{[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(cyclohexyl)amino]ethyldihydrogen phosphate;2-[(3-{[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(ethyl)amino]ethyldihydrogen phosphate;3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyldihydrogen phosphate;1-[3-({4-[(2-{[(3-chloro-4-fluorophenyl)amino]methyl}pyrimidin-5-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]piperidin-4-yldihydrogen phosphate;3-[(3-{[4-({2-[(3-chloro-4-fluorobenzyl)oxy]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)amino]-3-methylbutyldihydrogen phosphate;2-[(3-{[4-({2-[(3-chlorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}propyl)(2,2-dimethylpropyl)amino]ethyldihydrogen phosphate;[2-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)cyclopropyl]methyldihydrogen phosphate; and2-[4-({[4-({2-[(3-chloro-4-fluorobenzoyl)amino]pyrimidin-5-yl}amino)-6-methoxyquinazolin-7-yl]oxy}methyl)piperidin-1-yl]ethyldihydrogen phosphate; or a pharmaceutically acceptable salt thereof. 11.A pharmaceutical composition comprising a compound according to claim 1or a pharmaceutically acceptable salt thereof in association with apharmaceutically acceptable diluent or carrier. 12-15. (canceled)
 16. Amethod of treating a human suffering from a disease in which theinhibition of one or more Aurora kinases is beneficial to the treatment,comprising the steps of administering to a person in need thereof atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 17. A method of treating ahuman suffering from colorectal, breast, lung, prostate, pancreatic orbladder and renal cancer or leukemias or lymphomas, comprising the stepsof administering to a person in need thereof a therapeutically effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 18. A process for the preparation of a compoundof formula (I) according to claim 1 or a pharmaceutically acceptablesalt thereof, which process comprises converting a compound of formula(II) into a compound of formula (I) by phosphorylation of an appropriatehydroxy group:

where A, X, m, Y, R³ and R⁴ are as defined for formula (I); and Z′ is agroup selected from —NR^(1′) R^(2′), hydroxy, C₃₋₆cycloalkyl whichC₃₋₆cycloalkyl is substituted by hydroxy or C₁₋₄alkyl substituted byhydroxy, and a 4- to 7-membered ring linked via a carbon atom,containing a nitrogen atom and optionally containing a further nitrogenatom, which ring may be saturated, unsaturated or partially saturatedand which ring is substituted on carbon or nitrogen by hydroxy orC₁₋₄alkyl substituted by hydroxy and which ring is optionally furthersubstituted on carbon or nitrogen by 1, 2 or 3 halo or C₁₋₄alkyl groups;R¹ is a group selected from —COR^(8′), —CONR^(8′)R⁹ and C₁₋₆alkyl whichC₁₋₆alkyl is substituted by hydroxy and optionally further substitutedby 1 or 2 halo or methoxy groups; R^(2′) is a group selected fromhydrogen, —COR¹⁰, —CONR¹⁰OR¹¹ and C₁₋₆alkyl which C₁₋₆alkyl isoptionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxy groups,—S(O)_(p)R¹¹ (where p is 0, 1 or 2) or hydroxy, or R^(2′) is a groupselected from C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkylC₁₋₄alkyl; or R^(1′) and R^(2′) together with the nitrogento which they are attached form a 4- to 7-membered ring optionallycontaining a further nitrogen atom which ring may be saturated,unsaturated or partially saturated and which ring is substituted oncarbon or nitrogen by a group selected from hydroxy and C₁₋₄alkyl whichC₁₋₄alkyl is substituted by hydroxy or —NR^(8′)R⁹ and which ring isoptionally further substituted on carbon or nitrogen by 1, 2 or 3 haloor C₁₋₄alkyl groups; and where R^(8′) is C₁₋₄alkyl substituted byhydroxy and optionally further substituted by 1 or 2 halo or methoxygroups: and thereafter if necessary: i) converting a compound of theformula (I) into another compound of the formula (I); and/or ii)removing any protecting groups; and/or iii) forming a pharmaceuticallyacceptable salt thereof.
 19. The method according to claim 16 whereinAurora kinase is Aurora-A kinase or Aurora-B kinase.
 20. A compoundaccording to claim 1 wherein A is a group of formula (b) or (d):

where * is the point of attachment to the X group of formula (I) and **is the point of attachment to the Y group of formula (I); X is NH; m is0, 1, 2, 3 or 4: Y is a group selected from O, NR⁵CO, CONR⁵, CR⁶R⁷CONR⁵and CR⁶R⁷NR⁵: Z is a group selected from —NR¹R², phosphonooxy,C₃₋₆cycloalkyl which C₃₋₆cycloalkyl is substituted by phosphonooxy orC₁₋₄alkyl substituted by phosphonooxy, and a 4- to 7-membered ringlinked via a carbon atom containing a nitrogen atom and optionallycontaining a further nitrogen atom, which ring may be saturated,unsaturated or partially saturated which ring is substituted on carbonor nitrogen by phosphonooxy or C₁₋₄alkyl (substituted by phosphonooxy)and which ring is optionally further substituted on carbon or nitrogenby 1, 2 or 3 halo or C₁₋₄alkyl groups; R¹ is a group selected from—COR⁸, —CONR⁸R⁹ and C₁₋₆alkyl which C₁₋₆alkyl is substituted byphosphonooxy and optionally further substituted by 1 or 2 halo ormethoxy groups; R² is a group selected from hydrogen, —COR¹⁰, —CONR¹⁰R¹¹and C₁₋₆alkyl which C₁₋₆alkyl is optionally substituted by 1, 2 or 3halo or C₁₋₄alkoxy groups, —S(O)_(p)R¹¹ (where p is 0, 1 or 2) orphosphonooxy, or R² is a group selected from C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl; or R¹ and R² together withthe nitrogen to which they are attached form a 4- to 7-membered ringoptionally containing a further nitrogen atom which ring may besaturated, unsaturated or partially saturated which ring is substitutedon carbon or nitrogen by a group selected from phosphonooxy andC₁₋₄alkyl substituted by phosphonooxy or —NR⁸R⁹, and which ring isoptionally further substituted on carbon or nitrogen by 1, 2 or 3 haloor C₁₋₄alkyl groups, R³ is a group selected from hydrogen, halo, cyano,nitro, C₁₋₆alkoxy, C₁₋₆alkyl, —OR¹², —CHR¹²R¹³—OC(O)R¹², —C(O)R¹²,—NR¹²C(O)R¹³, —C(O)NR¹²R¹³, —NR¹²SO₂R¹³ —NR¹²R¹³; R⁴ is phenyl or benzyloptionally substituted by 1 or 2 of fluoro or chloro: R⁵ is a groupselected from hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₃₋₆cycloalkyl and C₃₋₆cycloalkylC₁₋₄alkyl; R⁶ and R⁷ are independentlyselected from hydrogen, halo, C₁₋₄alkyl, C₃₋₆cycloalkyl, hydroxy andC₁₋₄alkoxy; R⁸ is C₁₋₄alkyl substituted by phosphonooxy and optionallyfurther substituted by 1 or 2 halo or methoxy groups; R⁹ is selectedfrom hydrogen and C₁₋₄alkyl; R¹⁰ is selected from hydrogen and C₁₋₄alkylwhich C₁₋₄alkyl is optionally substituted by halo, C₁₋₄alkoxy, S(O)_(q)(where a is 0, 1 or 2) or phosphonooxy; R¹¹, R¹² and R¹³ areindependently selected from hydrogen, C₁₋₄alkyl and heterocyclyl; or apharmaceutically acceptable salt thereof.
 21. A compound according toclaim 1, wherein: A is a group of formula (a), (b), (c) or (d)

where * is the point of attachment to the X group of formula (I) and **is the Point of attachment to the Y group of formula (I); X is NH; m is0, 1, 2, 3 or 4; Y is O, NR⁵CO or CR⁶R⁷NR⁵ Z is —NR¹R², phosphonooxy,cyclopropyl which cyclopropyl is substituted by C₁₋₄alkyl substituted byphosphonooxy, and a piperidine or piperazine ring linked via a carbonatom which ring is substituted on carbon or nitrogen by phosphonooxy orC₁₋₄alkyl substituted by phosphonooxy; R¹is C₁₋₅alkyl substituted byphosphonooxy; R² is a group selected from hydrogen, C₁₋₆alkyl whichC₁-₆alkyl is optionally substituted by 1, 2 or 3 halo or C₁₋₄alkoxygroups, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkylC₁₋₄alkyl; R³ is C₁₋₄alkoxy or hydrogen: R⁴ is phenyl orbenzyl optionally substituted by 1 or 2 of fluoro or chloro; R⁵ ishydrogen or methyl: and R⁶ and R⁷ are independently hydrogen, fluoro,chloro or methyl; or a pharmaceutically acceptable salt thereof.
 22. Acompound according to claim 1, wherein: A is a group of formula (a),(b), (c) or (d)

where * is the Point of attachment to the X group of formula (I) and **is the point of attachment to the Y group of formula (I); X is NH; m is0, 1, 2, 3 or 4; Y is O, NR⁵CO or CR⁶R⁷NR⁵ Z is —NR¹R², phosphonooxy,cyclopropyl which cyclopropyl is substituted by C₁₋₄alkyl substituted byPhosphonooxy, and a piperidine or piperazine ring which the ring issubstituted by phosphonooxy or C₁₋₄alkyl substituted by Phosphonooxy; R¹and R² together with the nitrogen to which they are attached form aPiperidine, pyrrolidine or piperazine ring which ring is substituted oncarbon or nitrogen by a group selected from phosphonooxy,phosphonooxymethyl and 2-phosphonooxyethyl and which ring is optionallyfurther substituted on carbon or nitrogen by 1 or 2 methyl; R³ isC₁₋₄alkoxy or hydrogen: R⁴ is phenyl or benzyl optionally substituted by1 or 2 of fluoro or chloro; R⁵ is hydrogen or methyl; and R⁶ and R⁷ areindependently hydrogen, fluoro, chloro or methyl; or a Pharmaceuticallyacceptable salt thereof.
 23. A pharmaceutical composition comprising acompound according to claim 10 or a pharmaceutically acceptable saltthereof in association with a pharmaceutically acceptable diluent orcarrier.